HGNC Approved Gene Symbol: PAX6
SNOMEDCT: 44295002, 69278003, 715339004, 93390002; ICD10CM: H47.033, H47.31, H47.319, Q13.0, Q13.1, Q14.2; ICD9CM: 377.23, 743.45;
Cytogenetic location: 11p13 Genomic coordinates (GRCh38): 11:31,789,026-31,817,961 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p13 | ?Coloboma of optic nerve | 120430 | Autosomal dominant | 3 |
| ?Morning glory disc anomaly | 120430 | Autosomal dominant | 3 | |
| Aniridia | 106210 | Autosomal dominant | 3 | |
| Anterior segment dysgenesis 5, multiple subtypes | 604229 | Autosomal dominant | 3 | |
| Cataract with late-onset corneal dystrophy | 106210 | Autosomal dominant | 3 | |
| Foveal hypoplasia 1 | 136520 | Autosomal dominant | 3 | |
| Keratitis | 148190 | Autosomal dominant | 3 | |
| Microphthalmia/coloboma 12 | 120200 | Autosomal dominant | 3 | |
| Optic nerve hypoplasia | 165550 | Autosomal dominant | 3 |
PAX6, a member of the paired box gene family, encodes a transcriptional regulator involved in oculogenesis and other developmental processes. For a discussion of paired box domain genes, see 167410.
Based on the map location of the aniridia type II (106210) locus, Ton et al. (1991) cloned a candidate cDNA (D11S812E) that was completely or partially deleted in 2 patients with aniridia. The smallest region of overlap between the 2 deletions, comprising less than 70 kb, encompassed the 3-prime coding region of the cDNA. This cDNA, which spanned over 50 kb of genomic DNA, detected a 2.7-kb message specifically within all tissues affected in aniridia. The predicted 422-amino acid polypeptide product possesses a paired domain, a homeodomain, and a serine/threonine-rich C-terminal domain, all structural motifs characteristic of certain transcription factors. All evidence pointed to D11S812E as being the AN2 gene.
The PAX6 gene encodes a transcriptional regulator that recognizes target genes through its paired-type DNA-binding domain. The paired domain is composed of 2 distinct DNA-binding subdomains, the N-terminal subdomain (NTS) and the C-terminal subdomain (CTS), which bind respective consensus DNA sequences. The human PAX6 gene produces 2 alternatively spliced isoforms that have the distinct structure of the paired domain. The insertion, into the NTS, of 14 additional amino acids encoded by exon 5a abolishes the DNA-binding activity of the NTS and unmasks the DNA-binding ability of the CTS. Thus, exon 5a appears to function as a molecular switch that specifies target genes (Azuma et al., 1999).
Gronskov et al. (2001) discovered an alternatively spliced form of PAX6.
Using evolutionary sequence comparison, DNaseI hypersensitivity analysis, and transgenic reporter studies, Kleinjan et al. (2001) identified a region more than 150 kb distal to the major PAX6 promoter P1 containing regulatory elements. Components of this downstream regulatory region drove reporter expression in distinct partial PAX6 patterns, suggesting that the functional PAX6 gene domain may extend far beyond the transcription unit.
Ton et al. (1992) isolated a structurally homologous murine embryonic cDNA. They detected a 2.7-kb transcript in the adult mouse eye and cerebellum and in human glioblastomas, suggesting a neuroectodermal involvement in the pathogenesis of Sey/AN. There was virtually complete segmental identity between the mouse and human proteins. Using fluorescence in situ hybridization (FISH) in cell lines from patients with aniridia, Fantes et al. (1992) found that the candidate aniridia gene is deleted, supporting the murine Pax6 homolog as a strong candidate for the AN2 gene.
Hanson and Van Heyningen (1995) reviewed the work on PAX6 in man, mouse, and Drosophila. A chronology was provided, beginning with identification of the 'paired' gene as a key regulator of segmentation in Drosophila in 1980 to the discovery by Halder et al. (1995) that ectopic expression of Drosophila Pax6 induces ectopic eye development. Wawersik and Maas (2000) reviewed the role of Pax6 and other genes in vertebrate and fly oculogenesis.
PAX6 is required for formation of the lens placode, an ectodermal thickening that precedes lens development. Zhang et al. (2002) found that Meis1 (601739) and Meis2 (601740) were developmentally expressed in mice in a pattern similar to that of Pax6. Biochemical and transgenic experiments revealed that Meis1 and Meis2 bound a specific 26-bp sequence in the Pax6 lens placode enhancer that was required for its activity. Pax6 and Meis2 exhibited a strong genetic interaction in lens development, and Pax6 expression was elevated in lenses of Meis2-overexpressing transgenic mice. When expressed in embryonic lens ectoderm, dominant-negative forms of Meis downregulated endogenous Pax6.
Hever et al. (2006) reviewed the expression patterns and complex interactions of 3 genes associated with the development of the eye, SOX2 (184429), OTX2 (600037), and PAX6, noting that these interactions may explain the significant phenotypic overlap between mutations at these 3 loci.
In studies in Xenopus laevis, Masse et al. (2007) demonstrated that overexpression of ectonucleoside triphosphate diphosphohydrolase-2 (ENTPD2; 602012), an ectoenzyme that converts ATP to ADP, resulted in increased expression of Pax6, Rx1, and Six3 (603714) and caused ectopic eye-like structures, with occasional complete duplication of the eye. In contrast, downregulation of endogenous ENTPD2 decreased Rx1 and Pax6 expression. Masse et al. (2007) concluded that ENTPD2 therefore acts upstream of these eye field transcription factors (EFTFs). To test whether ADP, the product of ENTPD2, might act to trigger eye development through P2Y1 receptors, selective in Xenopus for ADP, Masse et al. (2007) simultaneously knocked down expression of the genes encoding ENTPD2 and the P2Y1 receptor (601167). This prevented the expression of Rx1 and Pax6 and eye formation completely.
The developing human subventricular zone has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. As summarized by Hansen et al. (2010), cells expressing the transcription factor PAX6 are found in the OSVZ, unlike in rodent where PAX6 is expressed mainly by radial glial (RG) cells in the VZ. It has been suggested that PAX6+ cells in the OSVZ include both progenitor cells and postmitotic neurons. Hansen et al. (2010) examined sections of fetal cortex and found that greater than 90% of PAX6 cells in the human OSVZ coexpressed the neural stem/progenitor cell marker SOX2, and many also expressed the proliferation marker Ki67 (see 176741), indicating that most of them are progenitor cells. Further studies led Hansen et al. (2010) to estimate that about 40% of all OSVZ progenitors are RG cells. Hansen et al. (2010) found that OSVZ RG-like cells have a long basal process but, surprisingly, are nonepithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, Hansen et al. (2010) demonstrated that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. The authors also showed that inhibition of Notch (190198) signaling in OSVZ progenitor cells induces their neuronal differentiation. Hansen et al. (2010) speculated that the establishment of nonventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain.
Lin et al. (2016) isolated lens epithelial stem/progenitor cells (LECs) in mammals and showed that Pax6 and Bmi1 (164831) are required for LEC renewal. The authors designed a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Their method preserved endogenous LECs and their natural environment maximally, and regenerated lenses with visual function.
Chauhan et al. (2004) performed functional studies of 8 missense and 2 nonsense disease-causing mutations in PAX6 and its exon 5a isoform. They found unexpected pleiotropic effects in gene regulation not predicted by the PAX6 DNA crystal structure. Transactivation by PAX6 and the 5a isoform was dependent on the location of mutation, type of DNA-binding site, and cellular environment. Chauhan et al. (2004) concluded that activation by PAX6 and the 5a isoform is modulated by specific cellular environments and that moderate phenotypes associated with PAX6 missense mutations likely originate from abnormal protein function in a restricted number of ocular cell types.
Using a genomics approach, Bhinge et al. (2014) identified genomewide PAX6 binding sites in human neuroectodermal cells. PAX6 activated several transcription factors and microRNAs, including MIR135B (619560), by directly binding to proximal enhancers. PAX6 activated MIR135B during neuroectoderm development, and ectopic expression of MIR135B promoted differentiation toward neuroectoderm. MIR135B promoted neural conversion by inhibiting the TGF-beta (TGFB1; 190180) and BMP (see 112264) signaling pathways by directly binding target sites in the 3-prime UTRs of signaling receptors and signaling intermediates, resulting in suppression at the protein level.
Aniridia
Jordan et al. (1992) analyzed the PAX6 gene in cells lines from 2 cases of sporadic aniridia (106210) and identified a 2-bp insertion (607108.0001) in one and deletion of an exon (607108.0002) in the other.
Hanson et al. (1993) described 4 PAX6 point mutations in aniridia cases, both sporadic and familial. They suggested that the frequency at which PAX6 mutations are found is an indication that lesions in PAX6 account for most cases of aniridia.
Glaser et al. (1994) analyzed the PAX6 gene in a family with 3 distinct ocular phenotypes, and identified 2 different mutations: the mother, who had aniridia, was heterozygous for an R103X mutation (607108.0005), whereas the father, who had congenital cataracts and late-onset corneal dystrophy, was heterozygous for an S353X mutation (607108.0006). Their severely affected daughter, who had microcephaly, choanal atresia, and bilateral anophthalmia, was compound heterozygous for both mutations. The nonsense mutations truncated PAX6 within the N-terminal paired (codon 103) and C-terminal PST domains (codon 353), respectively. Glaser et al. (1994) demonstrated that the C-terminal PST domain, a 152-amino acid region rich in proline, serine, and threonine, functions as a transcriptional activator and that the mutant form has partial activity.
Martha et al. (1995) found 4 different mutations in PAX6 in 1 sporadic and 5 familial cases of aniridia: a previously reported mutation and 3 novel ones (607108.0008-607108.0010). In all 6 of the aniridia cases, the mutations were predicted to generate incomplete PAX6 proteins and supported the theory that aniridia is caused by haploinsufficiency of PAX6. Axton et al. (1997) screened DNA from 12 aniridia patients for PAX6 mutations and found a total of 10 mutations from 5 familial and 5 sporadic cases. Mutations were not found in the DNA from 2 patients without a family history. All 10 mutations found resulted in functional haploinsufficiency.
Prosser and van Heyningen (1998) reviewed PAX6 mutations. They commented that no locus other than 11p13 has been implicated in aniridia and that PAX6 is clearly the major, if not the only, gene responsible. Twenty-eight percent of identified PAX6 mutations are C-to-T changes as CpG dinucleotides, 20% are splicing errors, and more than 30% are deletion or insertion events. There is a noticeably elevated level of mutation in the paired domain compared to the rest of the gene. Increased mutation in the homeodomain is accounted for by the hypermutable CpG dinucleotide in codon 240. Very nearly all mutations appeared to have caused loss of function of the mutant allele, and more than 80% of exonic substitutions result in nonsense codons. Prosser and van Heyningen (1998) commented that in a gene with such extraordinarily high sequence conservation throughout evolution, there should be undiscovered missense mutations. These might be associated with unidentified phenotypes. They pointed out that olfactory system anomalies, cerebellar coordination problems, or pancreatic malfunction might be expected and that some mild mutations might give rise to a viable recessive phenotype, most likely in consanguineous families. They suggested that where human deduction failed to find other phenotypes, the creation of specific PAX6 mutations in mouse might help identify them. They cataloged 44 mutations in exons, the largest number of which were in exons 6 and 7 with 10 mutations each.
Hanson et al. (1999) reasoned that the extraordinary conservation of the PAX6 protein at the amino acid level among vertebrates predicts that pathologic missense mutations should be common even though they are rarely seen in aniridia patients. Approximately 92% of reported mutations of PAX6 in aniridia patients lead to premature termination of the protein, i.e., are nonsense, splicing, insertion, and deletion mutations, and only 2% lead to substitution of one amino acid by another (missense). This suggested a heavy ascertainment bias in the selection of patients for PAX6 mutation analysis and the possibility that the 'missing' PAX6 missense mutations underlie phenotypes distinct from classic aniridia.
Singh et al. (1998) studied the behavior of truncation mutants occurring in the C-terminal half of PAX6. These mutant proteins retain the DNA binding domain but lose most of the transactivation domain. Singh et al. (1998) demonstrated that these mutants are dominant-negative in transient transfection assays when they are coexpressed with wildtype PAX6. The dominant-negative effects result from the enhanced DNA-binding ability of these mutants. Kinetic studies of binding and dissociation revealed that various truncation mutants have 3- to 5-fold higher affinity to various DNA-binding sites when compared with the wildtype PAX6.
In a study of 27 Danish patients with an aniridia phenotype, Gronskov et al. (1999) identified 19 PAX6 mutations, 16 of which were novel. Gronskov et al. (2001) reported a strategy for the mutation analysis of aniridia cases resulting in the detection of mutations in 68% of sporadic cases and in 89% of familial cases. They also reported 4 novel mutations in PAX6.
Fantes et al. (1995) studied 2 aniridia pedigrees in which the disease segregated with chromosomal rearrangements that involved 11p13 but did not disrupt the PAX6 gene. They isolated YAC clones that encompass the PAX6 locus and found that, in both pedigrees, the chromosomal breakpoint is at least 85 kb distal to the 3-prime end of PAX6. In addition, the open reading frame of PAX6 was apparently free of mutations. Fantes et al. (1995) proposed that the PAX6 gene on the rearranged chromosome 11 is in an inappropriate chromatin environment for normal expression, and therefore that a 'position effect' is the underlying mechanism of the anomaly in these families. Crolla et al. (1996) described another case which also suggested position effect: sporadic aniridia with a translocation t(7;11). By fluorescence in situ hybridization they showed that the breakpoint in 11p13 lay between the PAX6 locus and a region approximately 100 kb distal to PAX6. No detectable deletion was found within PAX6, suggesting that the aniridia may have resulted from the distal chromatin domain containing either enhancers or regulators. Position effect variegation was reviewed by Karpen (1994).
Lauderdale et al. (2000) reported 2 submicroscopic de novo deletions of 11p13, located more than 11 kb from the 3-prime end of PAX6, that caused sporadic aniridia in unrelated patients. Clinical manifestations were indistinguishable from cases with chain-terminating mutations in the coding region. Using human-mouse retinoblastoma somatic cell hybrids, the authors showed that PAX6 is transcribed only from the normal allele but not from the deleted chromosome 11 homolog. Their findings suggested that remote 3-prime regulatory elements are required for initiation of PAX6 expression.
In a 13-year-old boy with aniridia, autism, and mental retardation, Davis et al. (2008) identified a 1.3-Mb deletion approximately 35 kb distal to the last exon of PAX6; the authors noted that the deletion included the 3-prime enhancer regions characterized by Lauderdale et al. (2000) as well as 6 neighboring genes (ELP4, 606985; DPH4, 611072; DCDC1, 608062; DCDC5; MPPED2; and IMMP1L 612323). The mutation was presumably inherited from the mother, who had aniridia as well as depression, anxiety, and social awkwardness; DNA was not available for analysis. The unaffected father did not carry the deletion. Davis et al. (2008) screened the last exon of PAX6 and the 3-prime UTR in 400 unrelated autism probands but did not identify any mutations.
Singh et al. (2001) identified 3 missense mutations, including 1 novel mutation, in the PST domain among aniridia patients. Functional assays using a luciferase reporter gene revealed that the novel mutation had normal transactivation activity but lower DNA binding through the paired domain than the wildtype. Another of the mutations resulted in the loss of DNA binding ability of the PAX6 homeodomain. Substitution analyses of the C-terminal glutamine-422 indicated that the polarity and charge of the side chain of the terminal amino acid influenced DNA binding of the homeodomain of intact PAX6.
Chao et al. (2003) identified mutations in the PAX6 gene, including 9 novel intragenic mutations in 30 patients with aniridia. One patient with WAGR syndrome (194072) had a deletion of chromosome 11p and had lost the paternal PAX6 allele. Seven patients had a mutation in the normal stop codon (TAA) (607108.0016). This change led to run-on into the 3-prime UTR and was located at a mutation hotspot. The mutations in all 30 patients were predicted to result in PAX6 haploinsufficiency. No correlation was observed between mutation sites and phenotypes.
In a boy with partial aniridia of the left eye presenting as a pseudocoloboma, Morrison et al. (2002) identified heterozygosity for a missense mutation in the PAX6 homeodomain (R242T; 607108.0022). Molecular analysis by D'Elia et al. (2006) revealed that the DNA-binding properties of the homeodomain and the paired domain were not altered; however, the mutation reduced sensitivity to trypsin digestion, resulting in increased mutant protein levels. D'Elia et al. (2006) suggested that the PAX6 R242T phenotype could be due to abnormal increase of PAX6 protein, in keeping with the reported sensitivity of the eye phenotype to increased PAX6 dosage (Schedl et al., 1996).
Atchaneeyasakul et al. (2006) described the ophthalmic findings and mutation analyses of the PAX6 gene in 10 Thai aniridia patients from 6 unrelated families. Mutation analysis demonstrated 4 different truncating mutations, 2 of which were de novo. All mutations resulted in loss of function of the PAX6 protein. Atchaneeyasakul et al. (2006) concluded that their data confirmed inter- and intrafamilial variable phenotypic manifestations of which the underlying mechanisms might be haploinsufficiency or dominant-negative mutations.
In a 6-year-old Caucasian boy with partial aniridia, mild balance disorder, hand tremor, and learning disability, Ticho et al. (2006) identified a splice site mutation (IVS2+2T-A; 607108.0024) in the PAX6 gene. Although the ocular features and learning disorder were suggestive of Gillespie syndrome (see 206700), the authors stated that the novelty of the PAX6 mutation and relative subtlety of neurologic findings argued against that conclusion.
In a 9.5-year-old girl with bilateral aniridia, ataxia, and mental retardation, Graziano et al. (2007) identified heterozygosity for a nonsense mutation in the PAX6 gene (W257X; 607108.0025). The authors noted that the patient lacked the festooned pupillary edge and tufting considered to be pathognomonic for Gillespie syndrome, and that she had other clinical manifestations that were atypical for Gillespie patients. In addition, Graziano et al. (2007) stated that it was difficult to evaluate the real prevalence of mental deficits in patients with PAX6 mutations because the focus of most investigations was on eye phenotypes, and further noted that the role of additional unknown genetic variants in this patient could not be excluded.
In a girl with aniridia (106210), microphthalmia, microcephaly, and cafe-au-lait macules, Henderson et al. (2007) identified heterozygous mutations in the PAX6 (R38W; 607108.0026), NF1 (R192X; 613113.0046), and OTX2 (Y179X; 600037.0004) genes. The PAX6 and NF1 mutations were inherited from her mother, and the OTX2 mutation was inherited from her father, who had previously been studied by Ragge et al. (2005). Henderson et al. (2007) noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects.
Robinson et al. (2008) performed conventional karyotyping and targeted FISH analysis in 125 consecutive patients with aniridia, including 74 sporadic and 24 familial patients, 14 with WAGR syndrome, and 13 with other malformations. Thirty-four patients (27%) were found to have chromosomal rearrangements or deletions; of the 91 remaining patients, 37 had DNA available for analysis, and PAX6 mutations were identified in 33 patients. Overall, 67 (94%) of 71 cases undergoing full mutation analysis had a mutation in the PAX6 genomic region; in 4 cases no mutation was identified.
In a 4-year-old boy with prenatally diagnosed trisomy 21 (190685) who had complex brain anomalies, neonatal diabetes mellitus, and microphthalmia, Solomon et al. (2009) identified compound heterozygosity for a nonsense (R240X; 607108.0009) and a missense mutation (R38W; 607108.0026) in the PAX6 gene. His mother, who was heterozygous for the nonsense mutation, had bilateral aniridia and other eye anomalies, and his father, who was heterozygous for the missense mutation, had subtle iris hypoplasia and corectopia as well as congenital cataract and microcornea. Solomon et al. (2009) noted that this was the second reported (see 607108.0005) and only known surviving patient with biallelic PAX6 mutations.
Sisodiya et al. (2001) performed brain MRI on 14 patients with aniridia and heterozygous PAX6 mutations and found absence of the anterior commissure (AC) without callosal agenesis in 10 subjects, hypoplasia of the AC in 2, and a normal-sized AC in 2. They concluded that PAX6 haploinsufficiency can result in disruption in axonal migration and lead to more widespread human neurodevelopmental anomalies. In a similar study of 24 subjects with ocular abnormalities and PAX6 mutations, including the 14 patients reported by Sisodiya et al. (2001), Mitchell et al. (2003) found absence of the pineal gland in 13 subjects and absence of the AC in 12. The authors noted that neither of these findings had been reported in Pax6 mutant mouse models.
Anterior Segment Dysgenesis 5 and/or Foveal Hypoplasia 1
Hanson et al. (1994) presented evidence that PAX6 is involved in other anterior segment malformations besides aniridia. They described a child with Peters anomaly (ASGD5; 604229), a major error in the embryonic development of the eye with corneal clouding with variable iridolenticulocorneal adhesions, in whom 1 copy of PAX6 was deleted. They also found that affected members in a family with dominantly inherited anterior malformations, including Peters anomaly, were heterozygous for an R26G mutation (607108.0004) in the PAX6 gene. In addition, they pointed out that a proportion of 'small eye' mice, heterozygous for a nonsense mutation in murine Pax6, have an ocular phenotype resembling Peters anomaly. Hanson et al. (1999) presented 4 novel PAX6 missense mutations, 1 associated with foveal hypoplasia and cataract (FVH1; 136520), 1 associated with 'atypical aniridia' that included ectopia pupillae (129750) as the predominant feature, and 2 in association with more recognizable aniridia phenotypes. All 4 mutations were located within the PAX6 paired domain and affected amino acids that are highly conserved in all known paired domain proteins.
Azuma et al. (1999) found a heterozygous val54-to-asp (V54D; 607108.0015) mutation in exon 5a, the first mutation to be identified in the splice variant region. The mutation was found in 4 pedigrees with Peters anomaly, congenital cataract, Axenfeld anomaly, and/or foveal hypoplasia. Functional analyses demonstrated that the V54D mutation slightly increased NTS binding and decreased CTS transactivation activity to almost half. All 4 pedigrees were Japanese and originated in and lived in a particular geographic area in or near Tokyo. One of the 4 patients represented a sporadic case, since neither of her parents had the mutation.
In affected members of a family with foveal hypoplasia, congenital nystagmus, and anterior segment anomalies (mainly iris hypoplasia or atypical coloboma), Vincent et al. (2004) identified a heterozygous splice mutation in the PAX6 gene (607108.0021).
Keratitis
Autosomal dominant keratitis (148190) is an eye disorder characterized chiefly by corneal opacification and vascularization and by foveal hypoplasia. The clinical findings overlap with those of aniridia. For this reason, Mirzayans et al. (1995) used the candidate gene approach to investigate whether mutations in the PAX6 gene are also responsible for this disorder. Significant linkage was found between 2 polymorphic loci in the PAX6 region and keratitis in a family with 15 affected members in 4 generations; peak lod score = 4.45 at theta = 0.00 with D11S914. By SSCP analysis and direct sequencing, a mutation was found at the splice acceptor site of PAX6 exon 11 (607108.0011). The predicted consequence was incorrect splicing, resulting in truncation of the PAX6 proline-serine-threonine activation domain. The Sey(Neu) mouse results from a mutation in the Pax6 exon 10 splice donor site that produces a PAX6 protein truncated from the same point as occurred in the family reported by Mirzayans et al. (1995). Therefore, the Sey(Neu) mouse is an authentic animal model of autosomal dominant keratitis. The finding that mutations in PAX6 underlie both autosomal dominant keratitis and Peters anomaly (607108.0004) implicated PAX6 broadly in human anterior segment malformations.
Other Ocular Phenotypes
Azuma et al. (2003) identified heterozygous mutations in the PAX6 gene (e.g., 607108.0017-607108.0020) in 8 pedigrees with optic nerve malformations, including coloboma (120430), morning glory disc anomaly (see 120430), optic nerve hypoplasia/aplasia (165550), and persistent hyperplastic primary vitreous (see 257910). A functional assay demonstrated that each mutation decreased the transcriptional activation potential of PAX6 through the paired DNA-binding domain. Four of the detected mutations affected PAX6-mediated transcriptional repression of the PAX2 (167409) promoter in a reporter assay. Because PAX2 gene mutations had been detected in papillorenal syndrome (120330), the authors suggested that alterations in PAX2 function by PAX6 mutations may affect phenotypic manifestations of optic nerve malformations.
Liang et al. (2011) summarized conflicting reported results on the association between PAX6 polymorphisms and myopia. They conducted a case-control study involving 1,083 individuals with myopia and 1,096 controls from a Chinese population in Taiwan. SNPs rs644242 and rs662702 had marginal significance (p = 0.063), and further analyses showed that these SNPs were associated with extreme myopia (less than -11 D). The OR for extreme myopia was 2.1 (empiric p = 0.007) for the CC genotype at rs662702 at the 3-prime UTR. A functional assay for rs662702 demonstrated that the C allele had a significantly lower expression level than did the T allele (p = 0.0001), thereby increasing the risk of myopia. Liang et al. (2011) noted that SNP rs662702 was predicted to be located in the microRNA-328 (613701) binding site, which might explain the differential allelic effect on gene expression.
In 2 brothers with microphthalmia, coloboma, and other ocular anomalies (MCOPCB12; 120200), Deml et al. (2016) identified heterozygosity for a missense mutation in the PAX6 gene (V256A; 607108.0027). The mutation was inherited from their unaffected mother, who appeared to be mosaic for the mutation.
From among 372 individuals with bilateral MAC in the Human Genome Unit (HGU) eye malformation cohort, Williamson et al. (2020) identified 17 patients from 15 families who were heterozygous for missense mutations in the PAX6 gene (see, e.g., 607108.0026 and 607108.0028-607108.0033). Six probands had de novo mutations and 2 probands inherited the mutation from an affected parent; no segregation information was available for the remaining families. Analysis of a group of 399 unrelated individuals from the HGU eye malformation cohort who had aniridia or other PAX6-associated ocular anomalies revealed 7 non-MAC patients from 3 families with heterozygous missense mutations in PAX6. The authors also reviewed likely causative PAX6 missense variants reported in the Deciphering Developmental Disorders study, and reported 7 patients with heterozygous mutations in PAX6 (see 607108.0004 and 607108.0033). Functional analysis showed reduced binding to known DNA targets with the mutant proteins compared to wildtype PAX6. Williamson et al. (2020) noted that the remarkable sequence diversity of in vivo PAX6 binding sites might result in variant-specific differential effects on both the degree and repertoire of target gene activation; however, they stated that molecular properties alone could not explain all of the phenotypic heterogeneity observed among PAX6 missense variants, noting that patients with the same variant exhibited very different phenotypes.
Cerebral Malformations
Bamiou et al. (2004) reported a 53-year-old woman who was heterozygous for a PAX6 mutation and had absence of the anterior commissure with a normal corpus callosum. Central auditory testing showed a severe left ear deficit in dichotic speech tasks. The authors concluded that the patient had decreased auditory interhemispheric transfer function and suggested a role for the PAX6 gene in the neurodevelopment of higher-order auditory processing. In a separate report, Bamiou et al. (2004) found that all of 8 patients with a PAX6 mutation had abnormal results in at least 2 of 5 central auditory tests that measure interhemispheric auditory transfer. Six patients had an absent or hypoplastic anterior commissure, and 3 had a hypoplastic corpus callosum. The left ear scores in the dichotic speech tests were significantly lower in patients with the PAX6 mutations compared to controls; right ear scores were normal in all patients.
Morell et al. (2007) analyzed auditory processing in 106 monozygotic and 33 dizygotic twin pairs; test score correlations indicated that dichotic listening ability is a highly heritable trait (h-squared = 0.73).
SIMO Sequence
In a panel of 60 patients with aniridia without PAX6 exonic mutations or large-scale chromosomal abnormalities, Bhatia et al. (2013) screened a selection of eye-related cis-regulatory elements and in 1 patient (see AN2, 617141) identified a de novo nucleotide variant within an ultraconserved sequence, SIMO, located 150 kb downstream of PAX6 within intron 9 of the ELP4 gene (606985.0001). Functional analysis demonstrated that the mutation disrupts an autoregulatory PAX6 binding site, causing loss of enhancer activity that results in defective maintenance of PAX6 expression.
Reviews
Van Heyningen and Williamson (2002) reviewed the molecular genetics of PAX6, integrating data from human disease as well as various animal models.
Hanson (2003) reviewed the spectrum of human PAX6 gene mutations, noting that 71% of the mutations could be predicted to result in a premature termination codon (37%, nonsense; 23%, frameshift; 11%, splice site), whereas 4% represented antitermination mutations. In-frame insertions or deletions made up 7% of PAX6 mutations. Missense mutations accounted for 18% of PAX6 mutations, and half of those were associated with aniridia and thus likely to show significant loss of function. Noting that missense mutations can potentially cause partial loss of function or gain of function, the author suggested that this might explain why the remaining missense mutations were associated with distinct eye phenotypes, including isolated foveal hypoplasia, ectopia pupillae, and Peters anomaly. Hanson (2003) also stated that the increased risk of developing Wilms tumor observed in sporadic aniridia patients is associated with hemizygous deletions that remove 1 copy of PAX6 as well as 1 copy of WT1, leaving the patient susceptible to a second hit in WT1; Wilms tumor was not observed in any nondeletion patients. In addition, the author noted that cis-acting regulatory elements downstream of the 3-prime end of the PAX6 gene have been identified that alter PAX6 expression.
'Small Eye' Phenotype
Lyon (1988) suggested that 'small eye' (Sey) in the mouse, which is on chromosome 2, may be homologous to aniridia type II (106210) inasmuch as there is a region of conserved homology of synteny between human 11p and mouse chromosome 2. This suggestion was corroborated by van der Meer-de Jong et al. (1990) who found through interspecies backcrosses for linkage mapping that the Sey gene lies between Fshb and Cas-1. In the human, AN2 lies between the 2 cognate genes, FSHB and CAT. Glaser et al. (1990) studied the Sey mutation by localizing in an interspecies backcross between Mus musculus/domesticus and Mus spretus, the region on mouse chromosome 2 carrying 9 evolutionarily conserved DNA clones from proximal human 11p. In Dickie's small eye, they found deletion of 3 clones that encompass the aniridia (AN2) and Wilms tumor susceptibility genes in man. Unlike their human counterparts, the heterozygous Dickie's small eye mice do not develop nephroblastomas. The homology of Sey and AN2 was established by the cloning of the AN2 gene in the human and its homolog in the mouse, and the demonstration of mutations in 3 independent Sey alleles (Hill et al., 1991). The mutations would predictably disrupt the function of the gene, which belongs to the Pax multigene family. This family of developmental genes was first described in Drosophila. A Pax gene referred to as Pax6 is identical to the mouse homolog of the candidate aniridia gene. Matsuo et al. (1993) found an internal deletion of about 600 bp in the Pax6 gene in rats homozygous for the small eye mutation. Deletion was due to a single base insertion that generated an abnormal 5-prime donor splice site. They showed that anterior midbrain crest cells in the homozygous embryos reached the eye rudiments but did not migrate any further to the nasal rudiments, suggesting that the Pax6 gene is involved in conducting migration of neural crest cells from the anterior midbrain.
Ramaesh et al. (2003) found that the corneal abnormalities in heterozygous Pax6 +/- Sey mice were similar to those in aniridia-related keratopathy in PAX6 heterozygous patients. The mice showed incursion of goblet cells, suggesting impaired function of Pax6 +/- limbal stem cells; abnormal expression of cytokeratin-12 (601687), which might result in greater epithelial fragility; and age-related corneal degeneration, which might reflect poor wound-healing responses to accumulated environmental insults. Ramaesh et al. (2003) suggested that these findings extended the relevance of this mouse model of human aniridia to include corneal abnormalities.
Ramaesh et al. (2006) tested whether the Pax6 +/- genotype affected corneal wound-healing responses, including stromal cell apoptosis, epithelial cell migration rate, and matrix metalloproteinase-9 (MMP9; 120361) secretion, in culture. They concluded that the cumulative effects of abnormal wound-healing responses, characterized by increased stromal cell apoptosis and reduced levels of MMP9 secretion, might contribute to the corneal changes in the Pax6 +/- mice.
Quiring et al. (1994) isolated a Drosophila gene that contains both a paired box and a homeobox and has extensive sequence homology to the mouse Pax6 gene that is mutant in small eye. They found that the Drosophila gene mapped to chromosome IV in a region close to the 'eyeless' locus (ey). Two spontaneous mutations contained transposable element insertions into the cloned gene and affected gene expression, particularly in the eye primordia, thus establishing that the cloned gene encodes 'ey.' The finding that ey of Drosophila, small eye of the mouse, and human aniridia are encoded by homologous genes suggests that eye morphogenesis is under similar genetic control in both vertebrates and insects, in spite of the large differences in eye morphology and mode of development. Zuker (1994) noted that in his book 'On the Origin of Species,' Darwin dealt with the difficulties in explaining the evolution of organs of extreme perfection and complication and focused on the eye. Furthermore, Salvini-Plawen and Mayr (1977), in their study of the evolution of eyes, commented: 'It requires little persuasion to become convinced that the lens eye of a vertebrate and the compound eye of an insect are independent evolutionary developments.' The Drosophila compound eye is composed of 800 facets or ommatidia, each containing photoreceptor neurons, accessory cells, and a lens.
Schedl et al. (1996) generated YAC transgenic mice carrying the human PAX6 locus. When crossed onto the small eye background, the transgene rescued the mutant phenotype. Strikingly, mice carrying multiple copies on a wildtype background showed specific developmental abnormalities of the eye, but not of other tissues expressing the gene. Schedl et al. (1996) commented on the occurrence of abnormalities of the eye in patients with duplication of part of chromosome 11 including the PAX6 locus. The fact that simple overexpression of the human gene in transgenic mice causes abnormalities is encouraging for the generation of mouse models for human trisomies. They noted that generation of transgenics carrying large fragments of DNA should make it possible to narrow it down and identify genes responsible for particular aspects of trisomic phenotypes. Kleinjan et al. (2001) reported that a 310-kb YAC clone terminating just 5-prime of the common human PAX6 breakpoint failed to influence the small eye phenotypes, unlike the 420-kb YAC clone reported by Schedl et al. (1996). Kleinjan et al. (2001) identified a region more than 150 kb distal to the major PAX6 promoter P1 containing regulatory elements.
Thaung et al. (2002) carried out a genomewide screen for novel N-ethyl-N-nitrosourea-induced mutations that give rise to eye and vision abnormalities in the mouse, and identified 25 inherited phenotypes that affect all parts of the eye. A combination of genetic mapping, complementation, and molecular analysis revealed that 14 of these were mutations in genes previously identified to play a role in eye pathophysiology, namely Pax6, Mitf (156845), Egfr (131550), and Pde6b (180072). Many of the others were located in genomic regions lacking candidate genes.
Oculogenesis
In the guinea pig, zeta-crystallin (123691) achieves high expression specifically in lens through use of an alternative promoter. Richardson et al. (1995) showed that the Pax6 protein binds a site in this promoter that is essential for lens-specific expression. Lens and lens-derived cells exhibited a tissue-specific pattern of alternative splicing of Pax6 transcripts, and Pax6 was expressed in adult lens and cells that support zeta-crystallin expression. These results suggested that zeta-crystallin is a natural target gene for Pax6 and that this Pax family member has a direct role in the continuing expression of tissue-specific genes.
Using the Cre/loxP approach, Ashery-Padan et al. (2000) inactivated mouse Pax6 specifically in the eye surface ectoderm at the time of lens induction. Expression of Pax6 was detected in the surface ectoderm at embryonic day 9 (E9) but was no longer detectable by E9.5. Although lens induction occurred in the mutant, as indicated by Sox2 upregulation in the surface ectoderm, further development of the lens was arrested. Hence, Pax6 activity was found to be essential in the specified ectoderm for lens placode formation.
The molecular mechanisms mediating the retinogenic potential of multipotent retinal progenitor cells (RPCs) are poorly defined. Prior to initiating retinogenesis, RPCs express a limited set of transcription factors implicated in the evolutionary ancient genetic network that initiates eye development. Marquardt et al. (2001) elucidated the function of one of these factors, Pax6, in the RPCs of the intact developing mouse eye by conditional gene targeting. Upon Pax6 inactivation, the potential of RPCs became entirely restricted to only one of the cell fates normally available to RPCs, resulting in the exclusive generation of amacrine interneurons. These findings demonstrated that Pax6 directly controls the transcriptional activation of retinogenic basic helix-loop-helix factors that bias subsets of RPCs toward the different retinal cell fates, thereby mediating the full retinogenic potential of RPCs.
Vertebrates primarily express 2 alternatively spliced isoforms of PAX6 that differ by the presence or absence of exon 5a that encodes an additional 14 amino acid residues within the paired domain. The isoform containing the extra exon is specific to and conserved in vertebrates. To determine the role of the exon 5a isoform, Singh et al. (2002) generated mice that lacked the extra exon of the Pax6 gene. Unlike Pax6-null mice that exhibit anophthalmia with central nervous system defects and lethality, 5a isoform-null mice had iris hypoplasia and defects in the cornea, lens, and retina. Although invertebrates have structures that respond to light intensity and act to restrict light exposure of the eyes, a significant and distinct feature of the vertebrate eye is its ability to regulate the amount of incoming light through contractile pupils. This feature of the eye not only allows vertebrates to see in various light conditions but also enhances image resolution. The requirement of the 5a isoform in iris formation suggests that the evolution of this isoform contributed to advanced features of the vertebrate eye.
Dominguez et al. (2004) presented evidence that the organizing signal Notch (190198) does not promote growth in eyes of Drosophila through either 'eyeless' (ey) or 'twin of eyeless' (toy), the 2 Pax6 transcription factors. Instead, it acts through 'eyegone' (eyg), which has a truncated paired domain consisting of only the C-terminal subregion. In humans and mice, the sole PAX6 gene produces the exon 5a isoform by alternative splicing; like eyegone, this isoform binds DNA through the C terminus of the paired domain. Overexpression of the human PAX6 exon 5a isoform induces strong overgrowth in vivo, whereas the canonical PAX6 variant hardly effects growth. These results showed that growth and eye specification are subject to independent control and explained hyperplasia in a new way. Mann (2004) interpreted the significance of these findings. Whereas 2 distinct Pax genes control tissue growth and identity, respectively, in fly eye development, these 2 functions are encoded by distinct isoforms of the human gene PAX6.
Azuma et al. (2005) showed that overexpression of the exon 5a Pax6 isoform (Pax6+5a) in developing chick eye induced ectopic differentiation of retina-like structure. Pax6(+5a) point mutations found in patients with foveal hypoplasia (see V54D; 607108.0015) were unable to induce these ectopic retina-like structures. The authors proposed that Pax6(+5a) may induce a developmental cascade in the prospective fovea, area centralis, or visual streak region that leads to the formation of a retinal architecture bearing densely packed visual cells.
Azuma et al. (2005) showed in transfected chick embryos that Pax6 alone was sufficient to induce transdifferentiation of ectopic neural retina (NR) from retinal pigment epithelial (RPE) cells without addition of FGFs or surgical manipulation. Pax6-mediated transdifferentiation could be induced even at later stages of development. Both in vivo and in vitro studies showed that Pax6 lies downstream of FGF signaling, highlighting the central roles of Pax6 in NR transdifferentiation.
Davis-Silberman et al. (2005) used the Cre/loxP system to study the tissue-specific sensitivity of a single Pax6 allele in either the lens/cornea or the distal optic cup. Inactivation of a single Pax6 allele in the lens recapitulated the small-eye lens and corneal defects, while only mildly affected iris morphology in a non-cell-autonomous fashion. Conversely, selective inactivation of a single Pax6 allele in the distal optic cup revealed primarily cell-autonomous dosage requirements for proper iris differentiation, with no effects on either lens or corneal morphology. Pax6 dosage within the distal optic cup was found to influence the number of progenitors destined for the anterior ocular structures, the timing of iris muscle-cell differentiation, and iris stroma development.
Bandah et al. (2007) noted that the retina of some avian species contains 2 macular regions, making it an excellent model for retinal, and especially macular, development. They performed a comprehensive analysis of Pax6 expression in the pigeon retina and identified 41 transcripts encoding 17 protein isoforms produced by alternative splicing and alternative initiation of transcription. The expression levels of these transcripts in different retinal regions suggested their involvement in macular development.
Li et al. (2007) created and examined Pax6 mutant mouse chimeras from postnatal day (P) 0 to P10. They found that Sey/Sey retinal neurons did not survive past birth. A small population of Pax6-null cells was found in the retina that contributed to the blood vessel-associated cells that have their origins outside the retina. Furthermore, in contrast to previous reports, Sey/+ cells did contribute to the lens epithelium and Sey/Sey cells did not contribute to the anterior retinal pigment epithelium.
To investigate in which cell types both alleles of Pax6 need to be expressed to control the development of the tissues in the iridocorneal angle, Kroeber et al. (2010) inactivated a single Pax6 allele in either the lens and cornea or the distal optic cup of mice. Somatic inactivation of 1 allele of Pax6 exclusively from epithelial cells of lens and cornea resulted in the disruption of trabecular meshwork and Schlemm canal development as well as in the adhesion between iris periphery and cornea in juvenile eyes, which resulted in the complete closure of the iridocorneal angle in the adult eye. Structural changes in the iridocorneal angle presumably caused a continuous increase in intraocular pressure leading to degenerative changes in optic nerve axons and to glaucoma. In contrast, the inactivation of a single Pax6 allele in the distal optic cup did not cause obvious changes in iridocorneal angle formation. The authors concluded that the defects in iridocorneal angle formation are caused by nonautonomous mechanisms due to Pax6 haploinsufficiency in lens or corneal epithelial cells, and that Pax6 probably controls the expression of signaling molecules in lens cells that regulate the morphogenetic processes during iridocorneal angle formation.
Pancreatic Development
The islets of Langerhans, the functional units of the endocrine pancreas, are nested within the exocrine tissue of the pancreas and are composed of alpha-, beta-, delta-, and gamma-cells. Beta-cells produce insulin and form the core of the islet, whereas alpha-, delta-, and gamma-cells are arranged at the periphery of the islet and secrete glucagon (138030), somatostatin (182450), and a pancreatic polypeptide (167780), respectively. Pancreas development is known to be abolished in mice with a mutation in insulin promoter factor 1 (IPF1; 600733); in mice with a mutation for this gene, pancreas development is abolished, while mutations in the human gene cause congenital pancreatic agenesis (260370). Mice mutant in the Pax4 gene (167413) lack insulin-producing beta-cells. St-Onge et al. (1997) contributed to the knowledge concerning the molecular and genetic factors regulating lineage of the different endocrine cells. They showed that the Pax6 gene is expressed during the early stages of pancreatic development and in mature endocrine cells. The pancreas of Pax6 homozygous mutant mice lacked glucagon-producing cells, suggesting to the authors that PAX6 is essential for the differentiation of alpha-cells. The authors concluded that since mice lacking both PAX4 and PAX6 failed to develop any mature endocrine cells, both genes are required for endocrine fate in the pancreas.
Sander et al. (1997) presented genetic and biochemical evidence that PAX6 is a key regulator of pancreatic islet hormone gene transcription and is required for normal islet development. In mouse embryos homozygous for a mutant allele of the Pax6 gene (small eye), the numbers of all 4 types of endocrine cells in the pancreas were decreased significantly, and islet morphology was abnormal. Production of hormones, particularly glucagon, was markedly reduced because of decreased gene transcription. Biochemical studies identified wildtype PAX6 protein as the transcription factor that binds to a common element in the glucagon, insulin, and somatostatin promoters, and showed that PAX6 transactivates the glucagon and insulin promoters.
Pituitary Development
Kioussi et al. (1999) demonstrated that in addition to its many other roles in development, PAX6 is involved in the development of the Rathke pouch and early anterior pituitary gland, and that its expression controls the established boundaries of somatotrope, lactotrope, and thyrotrope cell types. The absence of Pax6 led to a marked increase of the thyrotrope cell lineage, whereas the somatotrope and lactotrope cell lineage changes were much diminished. Kioussi et al. (1999) suggested that the transient dorsal expression of PAX6 is essential for establishing a sharp boundary between dorsal and ventral cell types, based on the inhibition of Shh ventral signals.
Cushman and Camper (2001) reviewed the molecular basis of pituitary dysfunction in mouse and human. They listed 12 transcription factors critical for pituitary development and function, including PAX6. They cited the work of Kioussi et al. (1999) in which changes in the pituitary were found in the Pax6 knockout mouse model.
Central Nervous System Development
Glaser et al. (1994) demonstrated that the pattern of malformations in a human compound heterozygote was similar to that in the homozygous Sey mouse and suggested that PAX6 plays a critical role in controlling the migration and differentiation of specific neuronal progenitor cells in the brain.
The contribution of extrinsic and genetic mechanisms in determining areas of the mammalian neocortex has been a contested issue. Bishop et al. (2000) analyzed the roles of the regulatory genes Emx2 (600035) and Pax6, which are expressed in opposing gradients in the neocortical ventricular zone, in specifying areas. Changes in the patterning of molecular markers and area-specific connections between the cortex and thalamus suggested that arealization of the neocortex is disproportionately altered in Emx2 and Pax6 mutant mice in opposing manners predicted from their countergradients of expression: rostral areas expanded and caudal areas contracted in Emx2 mutants, whereas the opposite effect was seen in Pax6 mutants. Bishop et al. (2000) concluded that Emx2 and Pax6 cooperate to regulate arealization of the neocortex and to confer area identity to cortical cells.
By analyzing gene expression in various mouse mutants, Scardigli et al. (2001) concluded that Pax6 regulates Neurog2 (606624) expression in the spinal cord by controlling distinct Neurog2 enhancer elements that are active at different positions along the dorsoventral axis.
Radial glial cells, ubiquitous throughout the developing central nervous system, guide radially migrating neurons and are the precursors of astrocytes. Evidence indicates that radial glial cells also generate neurons in the developing cerebral cortex. Heins et al. (2002) demonstrated that radial glial cells isolated from the cortex of Pax6 mutant mice have a reduced neurogenic potential, whereas the neurogenic potential of nonradial glial precursors is not affected. Consistent with defects in only one neurogenic lineage, the number of neurons in the Pax6 mutant cortex in vivo is reduced by half. Conversely, retrovirally mediated Pax6 expression instructs neurogenesis even in astrocytes from postnatal cortex in vitro. Heins et al. (2002) concluded that PAX6 plays an important role as intrinsic fate determinant of the neurogenic potential of glial cells.
In a sporadic case of aniridia (106210), Jordan et al. (1992) demonstrated insertion of 2 extra bases, AG, resulting in frameshift and producing a stop codon, TAA, in the next exon. This was predicted to result in truncation of the protein with exclusion of the remaining C-terminal portion. The inserted bases created a new restriction site for the enzyme HinfI which led to the production of additional fragments on digestion of both DNA and RNA PCR products.
In a sporadic case of aniridia (106210) (cell line RUBAI), Jordan et al. (1992) identified a T-to-A transversion at position -6 of the splice acceptor site immediately 5-prime of exon G. Exon G was missing from the processed RNA, with exon F joined directly to exon H.
Davis and Cowell (1993) performed an SSCP analysis exon-by-exon of all 14 exons of the PAX6 gene in 6 families with aniridia (106210). In each family, band shifts were observed on the SSCP gels for only 1 exon, and direct PCR-sequencing revealed mutations in each case. Two mutations involved C-to-T transitions in CGA (arg) codons in exons 9 and 11, converting the codon to stop. Another C-to-T transition converted a CAG (gln) to a TAG (stop) in exon 7. A 2-bp insertion in exon 5 and a 1-bp insertion in exon 10 resulted in frameshift and premature termination in 2 further families. One of the 6 families showed an A-to-T mutation in the fourth position of the splice donor sequence in intron 5. This was the only mutation that was not identified by SSCP.
In a family with dominantly inherited anterior segment malformations with variable expression, including typical Peters anomaly (ASGD5; 604229) (family 3 of Holmstrom et al., 1991), Hanson et al. (1994) found a C-to-G transversion in nucleotide 438 (numbering according to Ton et al., 1991) in exon 5 of the PAX6 gene. (The C-to-G change was given as nucleotide 438 in the text, but nucleotide 439 in Figure 4 of Hanson et al. (1994).) The predicted result of this change would be the nonconservative replacement of arg26 with glycine. In the proband, the phenotype was that of Peters anomaly, while the phenotype of 2 other members of the family, his mother and his sister, most closely resembled the Rieger anomaly (see 180500). Hanson et al. (1994) pointed to published pedigrees illustrating the considerable variations in expressivity of both aniridia (see 106210) and anterior segment defects. Stone et al. (1976) and Beauchamp (1980) each reported a case of a child with an aniridia-like phenotype in one eye and a Peters-like phenotype in the other. A profusion of terms is used to describe these anterior segment malformations, e.g., anterior cleavage anomalies, mesenchymal dysgenesis, and anterior segment dysgenesis.
MICROPHTHALMIA/COLOBOMA 12
In 2 unrelated individuals (IDs 276121 and 277415 from the Deciphering Developmental Disorders database) with anterior segment anomalies and bilateral microphthalmia with iris coloboma (MCOPCB12; 120200), respectively, Williamson et al. (2020) reported heterozygosity for the R26G mutation (c.76C-G, ENST00000241001) in the PAX6 gene. Patient 277415 inherited the mutation from the affected mother, who had congenital cataract and optic nerve hypoplasia. Patient 277415 also exhibited extraocular anomalies, including delayed speech and language, choanal atresia, atrial septal defect, and nephrolithiasis.
In a family with 3 distinct ocular phenotypes, Glaser et al. (1994) identified 2 mutations in the PAX6 gene: the mother, who had classic aniridia (106210), was heterozygous for a CGA (arg103)-to-TGA (stop) mutation (R103X) within a CpG dinucleotide in exon 6, predicted to truncate PAX6 within the C-terminal half of the paired domain. The resulting 102-amino acid polypeptide could potentially bind DNA via the N-terminal half of the paired domain, but would lack the homeo- and PST-domains and therefore would almost certainly be nonfunctional. The father, who had a milder phenotype of congenital cataracts and late-onset corneal dystrophy (see 106210), was heterozygous for a TCA (ser353)-to-TGA (stop) mutation (S353X; 607108.0006) in exon 12, predicted to truncate PAX6 in the middle of the PST domain; the mutant form of the PST domain was shown to have partial activity. Their severely affected daughter, who had microcephaly, choanal atresia, and bilateral anophthalmia, was compound heterozygous for both mutations; she died on the eighth day of life.
For discussion of the ser353-to-ter (S353X) mutation in the PAX6 gene that was found in compound heterozygous state in a patient with congenital cataracts and late-onset corneal dystrophy (see 106210) by Glaser et al. (1994), see 607108.0005.
In affected members of a family in which the father and 2 children showed aniridia (106210), Hanson et al. (1995) found a G-to-C transversion in the last nucleotide of exon 12 leading to abnormality of splicing and skipping of exon 12. The wildtype exon 12 splice donor already differed from the consensus at position 3 and position 6; presumably the patient's mutation reduced the complementarity further so that the splice site was no longer recognized by the snRNA.
In a mother and daughter with aniridia (106210), Martha et al. (1995) found a C-to-T transition in exon 8 of the PAX6 gene, causing an arg203-to-ter (R203X) mutation. The mother had corneal changes.
In a father and son with aniridia (106210), Martha et al. (1995) found a C-to-T transition in exon 9 of the PAX6 gene, changing arginine-240 to a stop codon (R240X). The father was said to have macular agenesis in addition to glaucoma and cataracts. In a tabulation of PAX6 mutations, Prosser and van Heyningen (1998) pointed out that the R240X mutation resulting from a C-to-T transition in nucleotide 1080 in a hypermutable CpG nucleotide has been observed very frequently, with at least 10 independent reports.
In a 4-year-old boy with prenatally diagnosed trisomy 21 (190685) who had complex brain anomalies, neonatal diabetes mellitus, and microphthalmia, Solomon et al. (2009) identified compound heterozygosity for R240X and a missense mutation (R38W; 607108.0026) in the PAX6 gene. The proband's mother, who was heterozygous for R240X, had bilateral aniridia, glaucoma, corneal opacification, and a dense cataract in the right eye; she also had elevated fasting blood glucose. Autosomal dominant aniridia segregated in her family, with 5 additional affected individuals over 3 generations. The proband's father, who was heterozygous for R38W, had subtle iris hypoplasia and corectopia, congenital cataract, and microcornea, as well as high palate, dental crowding, and hearing loss. Cataract and hearing loss were present in 7 individuals over 3 generations in his family. No DNA was available from the proband's brother who died in infancy, who was described as having similar structural brain anomalies, clinical anophthalmia, and neonatal diabetes.
In a sporadic case of aniridia (106210) and in a family in which a mother and daughter were analyzed, Martha et al. (1995) found the same mutation in the 5-prime splice acceptor site of the PAX6 gene, between intron 11 and exon 12. This A-to-G transition at position -2 was predicted to result in deletion of exon 12.
In affected members of a family with autosomal dominant keratitis (148190) over 4 generations, originally reported by Pearce et al. (1995), Mirzayans et al. (1995) identified an A-to-T transversion in the exon 11 splice acceptor site of the PAX6 gene, predicted to result in aberrant splicing and the skipping of exon 11. The direct joining of exons 10 and 12 would result in exon 12 being read out of frame, producing a short nonsense peptide with a premature stop codon. A mutant PAX6 protein truncated for 117 amino acids from the C-terminal PAX6 proline-serine-threonine (PST) domain was expected in affected members of the family.
In affected members of a family with autosomal dominant isolated foveal hypoplasia (FVH1; 136520), Azuma et al. (1996) identified heterozygosity for a 799C-T transition in exon 7 of the PAX6 gene, resulting in an arg125-to-cys (R125C) missense mutation. The mutation occurred in the C-terminal part of the paired domain and was thought to be the first mutation identified in this region in any member of the PAX gene family. All affected family members had poorly defined foveal regions with normal-appearing anterior segments, including the iris. The foveal reflex was totally absent and retinal vessels were noted to cross the presumed foveal region.
In a male infant who was noted at birth to have ectopia pupillae (129750), Hanson et al. (1999) identified a heterozygous 739T-A transversion in the PAX6 gene, predicted to result in a val126-to-asp (V126D) substitution. At the age of 1 year, a full ophthalmologic examination showed mild limbal corneal dystrophy, punctate keratitis, optic nerve hypoplasia, and macular hypoplasia. The irides were hypoplastic with an irregular pupillary border and the crypts and collorette were absent. There were no abnormalities of the retinal vessels or lens. Psychomotor development was normal, a cerebral CT scan was normal, and there were no dysmorphic features. Both parents were completely normal ophthalmologically. PAX6 mutation analysis was indicated in this child because the corneal and retinal changes were similar to those seen in aniridia (106210). Hanson et al. (1999) considered this case to be an example of 'atypical aniridia.' The mutation, which occurred in the third alpha-helix of the C-terminal paired subdomain, was unexpectedly detected in a blood sample from the father; he was believed to be mosaic for this mutation.
Hanson et al. (1999) described a family in which the mother and a son and daughter had foveal hypoplasia and cataract (FVH1; 136520). PAX6 mutation analysis was indicated because of the presence of corneal and foveal abnormalities similar to those found in aniridia (106210). SSCP analysis followed by sequencing revealed a heterozygous 553G-T mutation, predicted to result in the substitution of glycine (GGC) by valine (GTC) at position 64, just beyond the third alpha-helix of the N-terminal paired subdomain. Glycine is absolutely invariant at this position in all paired domain proteins that had been characterized to that time. The proband had nystagmus and congenital bilateral cataracts. She had peripheral corneal vascularization and corneal epithelial changes similar to those seen in aniridia. She also had tilted optic discs and foveal hypoplasia. Her mother had congenital nystagmus with cataracts in addition to foveal hypoplasia and abnormalities of the peripheral corneal epithelium. Her brother had nystagmus from early infancy, and mild lens opacities were noted later.
In 3 Japanese families and in a sporadic Japanese case, Azuma et al. (1999) described a variety of eye anomalies caused by a heterozygous val54-to-asp (V54D) mutation in the PAX gene: anterior segment dysgenesis (ASGD5, 604229; Peters anomaly in 2 patients and Axenfeld anomaly in 1), congenital cataract, and/or foveal hypoplasia (see 136520). Two of the patients also had microphthalmia. In all of those affected, they identified a T-to-A transition at the twentieth nucleotide in exon 5a, resulting in a change of the seventh codon of the alternative splice region from GTC (val) to GAC (asp).
In 7 of 30 patients with aniridia (106210), Chao et al. (2003) found mutation of the normal stop codon 423 in the PAX6 gene from TAA (ter) to TTA (leu) (X423L). The change resulted in run-on into the 3-prime UTR. Two of the cases were familial and 5 were sporadic; 1 patient had developmental delay and 'autistic behavior,' and a CT scan showed brain asymmetry.
In a 5-year-old girl with bilateral morning glory disc anomaly (see 120430), Azuma et al. (2003) identified heterozygosity for a C-to-T transition at nucleotide 619 of the PAX6 gene, resulting in a pro68-to-ser (P68S) substitution.
In a 21-year-old male with bilateral optic nerve hypoplasia (165550), Azuma et al. (2003) identified heterozygosity for a C-to-T transition at nucleotide 1030 of the PAX6 gene, resulting in a gln205-to-ter (Q205X) substitution.
In a 1-year-old boy (patient 3) with iris anomaly, large chorioretinal and papillary coloboma, and a remnant of hyaloid vessel proliferation (MCOPCB12; 120200), Azuma et al. (2003) identified heterozygosity for a de novo c.1190T-C transition in exon 10 of the PAX6 gene, resulting in a phe258-to-ser (F258S) substitution at a highly conserved residue within the homeodomain. The mutation was not found in more than 100 control individuals. Analysis in mouse embryonic carcinoma P19 cells demonstrated significant impairment of paired domain (PD)-mediated transcriptional activity with the F258S mutant. The patient also exhibited growth retardation and impaired intellectual development.
In a 4-month-old girl with bilateral optic nerve aplasia (165550), Azuma et al. (2003) identified heterozygosity for an A-to-G transition at nucleotide 1588 of the PAX6 gene, resulting in a thr391-to-ala (T391A) substitution.
In affected members of a French family with foveal hypoplasia, congenital nystagmus, and anterior segment anomalies (mainly iris hypoplasia or atypical iris coloboma) (FVH1; 136520), Vincent et al. (2004) identified a heterozygous G-to-C transversion at position +5 of the consensus donor splice site of intron 4 of the PAX6 gene, resulting in skipping of exon 4. The mutant protein was predicted to contain a cryptic ATG initiation codon in exon 3 and a slightly altered paired domain in an open reading frame extended by 13 amino acids.
In a boy with partial aniridia of the left eye (106210) presenting as a pseudocoloboma, Morrison et al. (2002) identified heterozygosity for a 1087G-C transversion in the PAX6 gene, resulting in an arg242-to-thr (R242T) substitution in the homeodomain. There was no family history of congenital eye malformation. The right eye of the patient was completely normal, and the mutation was subsequently identified in blood DNA from his phenotypically normal mother, suggesting low penetrance.
Gel-retardation assays by D'Elia et al. (2006) revealed that the R242T homeodomain binds DNA as well as the wildtype homeodomain, and the mutation does not alter the DNA-binding properties of the paired domain. Cell transfection assays indicated that the steady state levels of the full-length mutant protein are higher than those of the wildtype protein. In vitro proteolysis assays showed that the mutation reduces sensitivity to trypsin digestion. D'Elia et al. (2006) suggested that the R242T phenotype could be due to abnormal increase of PAX6 protein, in keeping with the reported sensitivity of the eye phenotype to increased PAX6 dosage (Schedl et al., 1996).
In a mother and 2 sons with congenital aniridia (106210), ptosis, and slight mental retardation, Malandrini et al. (2001) identified a 719C-A transversion in exon 6 of the PAX6 gene, resulting in a ser119-to-arg (S119R) substitution. Malandrini et al. (2001) suggested that the missense mutation was responsible for both aniridia and ptosis, and possibly also for the cognitive dysfunction in this family.
In a 6-year-old Caucasian boy with partial aniridia (AN; 106210), mild balance disorder, hand tremor, and learning disability (AN; 106210), Ticho et al. (2006) identified heterozygosity for a de novo +2T-A transversion in intron 2 (IVS2+2T-A) of the PAX6 gene, resulting in ablation of the splice site. The mutation was not identified in either of the unaffected parents, in 100 control DNA samples, or in 117 DNA samples referred for PAX6 analysis.
In a 9.5-year-old girl with aniridia (AN; 106210), cerebellar ataxia, and mental retardation, Graziano et al. (2007) identified heterozygosity for a de novo 1133G-A transition in exon 10 of the PAX6 gene, resulting in a trp257-to-ter (W257X) substitution at a conserved residue in the third helix of the homeodomain. The mutation was not found in either parent. The authors noted that the role of additional unknown genetic variants in this patient could not be excluded.
Aniridia
In a girl with aniridia (106210), microphthalmia, microcephaly, and cafe-au-lait macules, Henderson et al. (2007) identified heterozygosity for a 474C-T transition in exon 5 of the PAX6 gene, resulting in an arg38-to-trp (R38W) substitution at a highly conserved residue, as well as heterozygous mutations in the NF1 (R192X; 613113.0046) and OTX2 (Y179X; 600037.0004) genes. Her mother, who carried the NF1 and PAX6 mutations, had neurofibromatosis type I (NF1; 162200) with typical eye defects; in addition, although her eyes were of normal size, she had small corneas, and also had cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal hypoplasia with normal-sized pupils. The proband's father, who had multiple ocular defects (MCOPS5; 610125), had previously been studied by Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation. Henderson et al. (2007) noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects.
For discussion of the R38W mutation in the PAX6 gene that was found in compound heterozygous state in a patient with prenatally diagnosed trisomy 21 (190685) who had complex brain anomalies, neonatal diabetes mellitus, and microphthalmia by Solomon et al. (2009), see 607108.0009.
Microphthalmia/Coloboma 12
In 2 unrelated individuals (patients 1273 and 355 in the Human Genetics Unit eye malformation cohort) with bilateral iris coloboma (MCOPCB12; 120200), Williamson et al. (2020) identified heterozygosity for a c.112C-T transition (c.112C-T, NM_000280.4) that resulted in an R38W substitution in the PAX6 gene.
In 2 brothers with microphthalmia, coloboma, and other ocular anomalies (MCOPCB12; 120200), Deml et al. (2016) identified heterozygosity for a c.767T-C transition (c.767T-C, NM_000280.4) in the PAX6 gene, resulting in a val256-to-ala (V256A) substitution at a highly conserved residue within the homeodomain. Sanger sequencing confirmed the mutation and indicated that their unaffected mother was likely mosaic for the variant, which was not found in the dbSNP, 1000 Genomes, EVS, or ExAC databases. Ocular anomalies in the brothers included bilateral microphthalmia, iris hypoplasia, sclerocornea, aphakia or lens subluxation, coloboma of the optic disc, and congenital glaucoma. Both also exhibited extraocular features, including low-set prominent ears and microcephaly in the proband, and asymmetric facies and a history of mild developmental delays which resolved in his younger brother. The authors noted that an ENU mutagenesis project by Thaung et al. (2002) had identified a mouse Pax6 mutation (V270E) at the corresponding residue to V256; the mice with the V270E mutation demonstrated normal-sized eyes, corneal dimple, and an irregular pupil.
In 2 unrelated patients (individuals 3190 and 1517 in the Human Genetics Unit eye malformation cohort) with microphthalmia, coloboma, and sclerocornea (MCOPCB12; 120200), who were negative for mutation in the SOX2 (184429) and OTX2 (600037) genes, Williamson et al. (2020) identified heterozygosity for a c.372C-A transversion (c.372C-A, NM_000280.4) in the PAX6 gene, resulting in an asn124-to-lys (N124K) substitution within the highly conserved paired domain. The mutation occurred de novo in both the patients. EMSA analysis demonstrated reduced binding of the N124K mutant to LE9 and SIMO elements, known DNA targets of PAX6, compared to the wildtype protein. Vision was severely impaired in these patients, who were nearly blind or had only light perception; other ocular anomalies present included unilateral aniridia in 1 patient, lens subluxation in both, and cataract in 1.
In 3 unrelated patients (individuals 1319, 339, and 5 in the Human Genetics Unit eye malformation cohort) with microphthalmia, coloboma, and sclerocornea (MCOPCB12; 120200), who were negative for mutation in the SOX2 (184429) and OTX2 (600037) genes, Williamson et al. (2020) identified heterozygosity for a c.372C-G transversion (c.372C-G, NM_000280.4) in the PAX6 gene, resulting in an asn124-to-lys within the highly conserved paired domain. The mutation occurred de novo in 1 patient; DNA was unavailable for testing from the remaining probands' relatives. EMSA analysis demonstrated reduced binding of the N124K mutant to LE9 and SIMO elements, known DNA targets of PAX6, compared to the wildtype protein. Vision was severely impaired in these patients, who were blind or had only light perception; other ocular anomalies included lens subluxation in 1, cataract in 1, retinal detachment and pthisis in 2, and possible morning glory defect of the optic nerve in 1.
In a 7-month-old boy (patient 3189 in the Human Genetics Unit eye malformation cohort) with severe bilateral microphthalmia and sclerocornea, who also had right congenital aphakia and small left lens presenting as a hypodense attachment to the cornea (MCOPCB12; 120200), who was negative for mutation in the SOX2 (184429) and OTX2 (600037) genes, Williamson et al. (2020) identified heterozygosity for a de novo c.160A-C transversion (c.160A-C, NM_000280.4) in the PAX6 gene, resulting in a ser54-to-arg (S54R) substitution within the highly conserved paired domain. His unaffected parents and brother did not carry the mutation. EMSA analysis demonstrated an 85% reduction in binding of the S54R mutant to LE9 and SIMO elements, known DNA targets of PAX6, compared to the wildtype protein.
In a young adult man (patient 494 in the Human Genetics Unit eye malformation cohort) with severe bilateral microphthalmia (MCOPCB12; 120200), who was negative for mutation in the SOX2 (184429) and OTX2 (600037) genes, Williamson et al. (2020) identified heterozygosity for a de novo c.162T-G transversion (c.162T-G, NM_000280.4) in the PAX6 gene, resulting in a ser54-to-arg (S54R) substitution within the highly conserved paired domain. The patient also exhibited downslanting palpebral fissures, protruding ears, microcephaly, mild mental retardation, and short stature. His unaffected parents and brother did not carry the mutation. EMSA analysis demonstrated an 85% reduction in binding of the S54R mutant to LE9 and SIMO elements, known DNA targets of PAX6, compared to the wildtype protein.
In a 10-year-old girl (patient 1016 in the Human Genetics Unit eye malformation cohort) with bilateral microphthalmia, anterior segment dysgenesis, congenital cataract, and microcornea (MCOPCB12; 120200), Williamson et al. (2020) identified heterozygosity for a c.113G-A transition (c.113G-A, NM_000280.4) in the PAX6 gene, resulting in an arg38-to-gln (R38Q) substitution within the highly conserved paired domain. She inherited the mutation from her 42-year-old father (patient 3343 in the HGU cohort), for whom limited clinical information was available but who was reported to have bilateral cataracts. Neuroimaging in the proband showed small optic nerves, chiasm, and tracts. Extraocular features included mildly reduced head circumference and autistic behaviors.
In a 4-year-old boy (patient 1141 in the Human Genetics Unit eye malformation cohort) and his 41-year-old father (patient 1139 in the HGU cohort) with bilateral microphthalmia and iris coloboma as well as congenital cataract (MCOPCB12; 120200), Williamson et al. (2020) identified heterozygosity for a c.77G-A transition (c.77G-A, NM_000280.4) in the PAX6 gene, resulting in an arg26-to-gln (R26Q) substitution within the highly conserved paired domain. Other features in the affected individuals included patchy iris hypoplasia and foveal hypoplasia with an aberrant retinal vessel pattern in the boy, and choroid coloboma, microcornea, nystagmus, and secondary glaucoma in the father. The authors also ascertained a patient from the Deciphering Developmental Disorders database (ID 265016) who was heterozygous for the R26Q variant and was diagnosed with congenital blindness, congenital cataract, and cone/cone-rod dystrophy. The mutation arose de novo in this patient.
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