Alternative titles; symbols
HGNC Approved Gene Symbol: WDR62
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:36,054,897-36,111,145 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.12 | Microcephaly 2, primary, autosomal recessive, with or without cortical malformations | 604317 | Autosomal recessive | 3 |
The WDR62 gene encodes a protein that localizes to the centrosome and to the nucleus, depending on the cell phase and on the cell type (summary by Bhat et al., 2011).
Bilguvar et al. (2010) identified the WDR62 gene in mutation analysis of a patient with microcephaly and cortical abnormalities. The WDR62 gene encodes a 1,523-amino acid protein. Immunohistochemical staining of human fetal brain at 20 weeks' gestation demonstrated enriched WDR62 expression within the ventricular and subventricular zones. Stainings suggested predominantly nuclear localization, which was confirmed by immunofluorescence microscopy and Western blot analysis. WDR62 is expressed by neural stem cells and intermediate progenitors, marked by SOX2 (184429) and TBR2 (604615) expression. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other microcephaly genes, WDR62 apparently does not associate with centrosomes.
Nicholas et al. (2010) noted that WDR62 contains at least 15 WD repeats. In HeLa, HEK293, and B lymphoblastoid cells, they found that WDR62 had weak, diffuse cytoplasmic expression and was not found in the nucleus during interphase. However, during mitosis, WDR62 accumulated strongly at the spindle poles, although it was not present at the midbody in cytokinesis. The expression pattern of WDR62 was identical to that of ASPM (605481), which is mutant in primary microcephaly-5 (MCPH5; 608716). Immunohistochemistry and confocal microscopy of mouse embryonic brain showed Wdr62 expression exclusively in apical precursors undergoing mitosis at the apical-ventricular surface in the neuroepithelium of the future cerebral cortex. Wdr62 expression was also found exclusively in intermediate neural precursors found in the subventricular zone during mitosis. Similar localization to mitotic neural precursor cells was observed in human embryonic brain tissue. WDR62 expression was also found in newborn neurons and in the outermost layer of neurons that had just migrated to the cortical plate.
Yu et al. (2010) found widespread expression of Wdr62 in the developing mouse brain, with highest expression in the forebrain. Expression was seen in the ventricular zone and cortical plate, consistent with roles in progenitor cells and postmitotic neurons.
By immunohistochemical analysis, Zhou et al. (2018) showed that Wdr62 protein was abundantly expressed in germ cells of mouse ovary and testis during the embryonic stage.
Bilguvar et al. (2010) determined that the WDR62 gene contains 32 exons.
There are alternative WDR62 transcripts in humans: exon 27 contains an in-frame intraexonic alternative splice acceptor site, resulting in the exclusion of the first 12 nucleotides (Nicholas et al., 2010).
The WDR62 gene maps to chromosome 19q13.12 (Bilguvar et al., 2010).
Yu et al. (2010) found notable cell-cycle dependent cellular localization of WDR62 in HeLa and HEK cells. During interphase, there was punctate, perinuclear expression, suggesting localization to the Golgi apparatus, whereas during M phase, WDR62 was found at the spindle poles. The subcellular localization resembled that of CEP170 (613023). The findings suggested a major centrosomal role for WDR62.
In cellular studies, Bhat et al. (2011) found that WDR62 localized to centrosomes throughout mitotic progression. No staining was observed at the midbody during cytokinesis. During interphase, WDR62 localized to nucleoli. The findings indicated that WDR62 is a centrosomal as well as a nuclear protein and that localization is dependent both on the cell phase and on the cell type.
Bilguvar et al. (2010) identified 2 missense, 2 nonsense, and 2 frameshift mutations (613583.0001-613583.0005) in the WDR62 gene in 10 patients with microcephaly-2 with cortical malformations (MCPH2; 604317). All patients were from consanguineous Turkish families and manifested with microcephaly, moderate to severe mental retardation, and cortical malformation including pachygyria with cortical thickening, microgyria, lissencephaly, hypoplasia of the corpus callosum, schizencephaly, and in 1 instance, cerebellar hypoplasia.
In affected members of 2 consanguineous Pakistani families with primary microcephaly showing linkage to chromosome 19q13 (MCPH2) (Roberts et al., 1999), Nicholas et al. (2010) identified 2 different homozygous mutations in the WDR62 gene (613583.0006 and 613583.0007, respectively). In 5 additional consanguineous families of Pakistani, Arab, and Caucasian ancestry with primary microcephaly, they identified 4 different homozygous WDR62 mutations (see, e.g., 613583.0008-613583.0009, 613583.0011). Overall, the findings indicated that WDR62 is a key protein in enabling spindle poles to position the cytokinetic furrow and prolong neural precursor generation, a process that is uniquely vital to the proper growth of the human cerebral cortex.
Yu et al. (2010) identified 6 different homozygous mutations in the WDR62 gene (see, e.g., 613583.0009-613583.0011) in affected members of 6 consanguineous families with microcephaly-2 with cortical malformations, including polymicrogyria, schizencephaly, and subcortical heterotopia.
Bhat et al. (2011) identified 2 different homozygous truncating WDR62 mutations in 2 unrelated consanguineous Indian families with MCPH2 with cortical malformations, bringing the total number of pathogenic mutations in the gene to 17. Six of the 17 mutations are missense, and mutations occur throughout the gene sequence. Bhat et al. (2011) emphasized the wide phenotypic spectrum of cortical malformations in mutation carriers.
Sgourdou et al. (2017) found that mice homozygous for a C-terminal truncating mutation in Wdr62 were viable but infertile. Compared with wildtype mice, mutant mice had smaller body size at early postnatal stages, but not in adulthood. Mutant mouse brain was smaller than normal from birth onward, likely due to reduced brain cell number. Cortical radial thickness was reduced in mutant mouse brain, and neocortical cytoarchitecture was disrupted, with dense and compact upper cortical layers, especially at rostral levels. Examination of microcephaly in mutant mice revealed that Wdr62 was required for proliferation of late-born cortical progenitors and differentially impacted self-renewal and differentiation of early versus late neocortical progenitors. Mutant mice exhibited asymmetric centrosome inheritance in neocortex, leading to abnormal migration and differentiation of mutant neurons inheriting the new mother centriole. Loss of Wdr62 in neural progenitors affected differentiation of a subset of cortical neurons. Wdr62 disruption was associated with defects in spindle pole localization of Wdr62 and abnormalities in mitotic cell cycle progression in neocortical progenitors from mutant mice and in primary fibroblasts from humans with autosomal recessive primary microcephaly and a similar C-terminal truncating mutation in WDR62. Database analysis and other investigation showed that wildtype WDR62, but not mutant WDR62, interacted with the core chromosome passenger complex (CPC) enzyme AURKB (604970).
Zhou et al. (2018) found that Wdr62 -/- mice were born at a normal mendelian ratio without developmental defects. However, Wdr62 -/- mice were completely infertile with reduced ovary and testis size and absent ovarian follicles in females. Immunofluorescence and real-time PCR analyses showed a defect in meiotic initiation in Wdr62 -/- female germ cells, causing them to remain in an undifferentiated state and undergo apoptosis. Expression of meiotic genes was dramatically reduced in germ cells from Wdr62 -/- female mice. Further analysis showed that Wdr62 was required for retinoic acid-induced meiotic gene expression by activating Jnk1 (MAPK8; 601158) signaling, and Jnk1 overexpression partially rescued defective germ cell development in Wdr62 -/- female mice.
Shohayeb et al. (2020) generated knockin mice homozygous for a val66-to-met (V66M) or arg439-to-his (R439H) mutation in Wdr62, corresponding to the human V65M (613583.0011) and R438H mutations (613583.0006) associated with microcephaly, as well as mice homozygous for a Wdr62 null allele (Wdr62-null mice). Expression of Wdr62 was maintained in R439H mice at both transcript and protein levels, was reduced only at the protein level in V66M mice, and was substantially reduced at both transcript and protein levels in Wdr62-null mice. Postnatal mice homozygous for R439H were rarely seen due to embryonic lethality during late gestation or lethality at birth, whereas mice homozygous for V66M or Wdr62 deletion were born at only marginally lower than expected mendelian ratios. However, each Wdr62 mutation resulted in gross morphologic defects consistent with ciliopathies (dwarfism, anophthalmia, and microcephaly). The Wdr62 mutations triggered premature differentiation and loss of self-renewed radial glia in mutant mice, as they perturbed division orientation of apical progenitors and increased cell cycle exit. Wdr62 played a conserved role in cilia regulation in developing cortex, and Wdr62 mutations caused axonemal and basal body defects, thereby disrupting normal cilia regulation in developing cortex. Wdr62 localized to the basal body of ciliated wildtype mouse embryonic fibroblasts (MEFs). Wdr62 mutants also localized to the basal body, but they lost their ability to interact with Cpap (CENPJ; 609279) and failed to recruit Cpap to centrosomes, leading to deficient recruitment of Ift88 (600595), a protein required for cilia formation, to basal bodies and ciliary axonemes. This loss of function in Wdr62 mutant mice caused premature differentiation of radial glia and cilia defects that contributed to development of microcephaly.
In 2 sibs with autosomal recessive microcephaly-2 and cortical malformations (MCPH2; 604317) and in an affected child from another family, all from consanguineous Turkish unions, Bilguvar et al. (2010) identified homozygosity for a 4-basepair deletion (TGCC) in exon 31 of the WDR62 gene. This deletion occurred at codon 1402 and resulted in a frameshift and premature termination (Val1402GlyfsTer12). The mutation was heterozygous in all parents. It was not observed in 1,290 Turkish control chromosomes. The index patient was a 4-year, 6-month-old female who initially presented at 4 months of age with small head size. At 2 years, 3 months she showed micrognathia and a bulbous nose, and suffered from severe mental retardation. She had had no seizures. MRI showed diffuse cortical thickening and pachygyria. The patient from the second family was a 2-year, 4 month-old male. He had microcephaly and developmental delay but no seizures. Coronal images of this patient showed findings of microlissencephaly including prominent microcephaly, bilateral Sylvian clefts, hypoplastic corpus callosum, and thickened cortex. The kinship coefficients between affected individuals from both families were consistent with fourth-degree relatedness.
In a 15-year, 5-month old female with microcephaly-2 and cortical malformations (MCPH2; 604317), the child of consanguineous Turkish parents, Bilguvar et al. (2010) identified homozygosity for a G-to-A substitution in exon 12 of the WDR62 gene, resulting in a glutamic acid-to-lysine substitution at codon 526 (E526K). The glutamic acid at codon 526 was invariant in all species examined from human to zebrafish and lamprey. This mutation was found in heterozygosity in 3 apparently unrelated neurologically normal Turkish individuals, giving an allele frequency of 0.2%. The patient presented to medical attention at age 3.5 years with poor verbal skills. She had microcephaly, severe mental retardation, prognathism, dysconjugate gaze, and dysarthria, and was able to ambulate independently. Although abnormal electroencephalograms were noted, the patient never suffered an overt seizure.
In 2 sibs and their cousin with microcephaly-2 and cortical malformations (MCPH2; 604317), Bilguvar et al. (2010) identified homozygosity for a missense mutation in the WDR62 gene, a G-to-C transversion in exon 6 that converted tryptophan to serine at codon 224 (W224S). All parents were heterozygous for the mutation, which was not identified in 1,290 Turkish and 1,500 Caucasian control chromosomes. Tryptophan-224 was invariant in all species examined from human to zebrafish and lamprey. The proband was a 6-year, 5-month-old boy who presented at 2 years of age with hyperactivity, seizures, and inability to sleep. He experienced 4 to 8 seizures per day and had microcephaly, micrognathia, and severe mental retardation, and could ambulate only with assistance. The sibs were cousins of the proband. One was an 8-year, 7-month-old female who presented at age 3 with seizures. She was microcephalic, hyperactive, and had dysconjugate gaze. She was able to walk independently and had no obvious dysmorphic features but had moderate mental retardation. Her brother was 12 years, 11 months old. He had seizures, self-mutilating behavior, and severe mental retardation, but could ambulate independently.
In a 14-year, 6-month-old male with microcephaly-2 and cortical malformations (MCPH2; 604317), the product of a consanguineous Turkish union, Bilguvar et al. (2010) identified homozygosity for a C-to-T transition in exon 11 of the WDR62 gene, resulting in a glutamine-to-termination substitution at codon 470 (Q470X). This mutation was not identified in 1,290 Turkish and 1,500 Caucasian control chromosomes. The patient was severely mentally retarded but had never had seizures. He had required surgery for hernia repair and cryptorchidism.
In a 10-year, 10-month-old female with microcephaly-2 and cortical malformations (MCPH2; 604317), the product of a consanguineous Turkish union, Bilguvar et al. (2010) identified homozygosity for a 17-bp deletion in exon 30 of the WDR62 gene, leading to a frameshift at codon 1280 and premature termination following a novel peptide of 20 amino acids (Gly1280AlafsTer21). The patient presented to medical attention at 3 months of age with failure to thrive and small head size. On neurologic examination she was noted to have good head control. She recognized her mother and had a social smile. This mutation was not identified in 1,290 Turkish and 1,500 Caucasian control chromosomes.
In affected members of a consanguineous Pakistani family with primary microcephaly-2 (MCPH2; 604317), originally reported by Roberts et al. (1999), Nicholas et al. (2010) identified a homozygous 1313G-A transition in exon 10 of the WDR62 gene, resulting in an arg438-to-his (R438H) substitution at a highly conserved residue. In vitro functional expression assays showed that the mutant protein did not localize correctly to the spindle poles during mitosis. The mutation was not found in 298 Pakistani control chromosomes. Brain scan from 1 patient showed a simplified gyral pattern.
In affected members of a consanguineous Pakistani family with primary microcephaly-2 (MCPH2; 604317), originally reported by Roberts et al. (1999), Nicholas et al. (2010) identified a homozygous 1-bp duplication (4241dupT) in exon 31 of the WDR62 gene, resulting in a frameshift and premature termination. The mutation was predicted to result in a stable transcript with C-terminal deletion of 109 amino acids in a region that contains neither predicted protein domains nor posttranslational modification sites. The mutation was not found in 298 Pakistani control chromosomes. In vitro functional expression assays showed that the mutant protein did not localize correctly to the spindle poles during mitosis. Brain scans of patients were not available.
In affected individuals from 2 unrelated Pakistani families with primary microcephaly-2 (MCPH2; 604317), Nicholas et al. (2010) identified a homozygous 1531G-A transition in exon 11 of the WDR62 gene, resulting in an asp511-to-asn (D511N) substitution at a highly conserved residue. The mutation was found in 1 of 284 Pakistani control chromosomes. Brain scans of the affected individuals were not available.
In a Turkish boy, born of consanguineous parents, with microcephaly-2 with cortical malformations (MCPH2; 604317), Yu et al. (2010) identified a homozygous 1-bp insertion (3936insC) in exon 30 of the WDR62 gene, resulting in a frameshift and premature termination. The mutation was not identified in 508 control individuals. The boy had severely delayed psychomotor development, and brain MRI showed polymicrogyria, simplified gyral pattern, volume loss, and a corpus callosum with incomplete genu and small splenium. A second pregnancy was terminated after the ultrasound showed microcephaly and abnormal gyral pattern in the fetus.
In a Caucasian girl, born of consanguineous parents, with microcephaly, thickened cerebral cortex, and severe developmental delay, Nicholas et al. (2010) identified homozygosity for the 3936insC mutation, which they termed 3936dupC. The mutation was not identified in 396 Caucasian control chromosomes.
In 3 affected Mexican sibs, born of consanguineous parents, with microcephaly-2 with cortical malformations (MCPH2; 604317), Yu et al. (2010) identified a homozygous 1-bp deletion (363delT) in exon 4 of the WDR62 gene, resulting in a frameshift and premature termination. The mutation was not identified in 508 control individuals. There was some phenotypic variability: 2 sibs had small heads with a simplified gyral pattern on brain MRI, 1 of whom had also had generalized tonic-clonic seizures and severe psychomotor retardation. The third sib did not have seizures but had more severe microcephaly (-5.4 SD), normal early psychomotor development with later delay, and more complex MRI changes, including a simplified gyral pattern, thin corpus callosum, and subcortical band heterotopia.
In 3 affected Saudi Arabian sibs, born of consanguineous parents, with microcephaly-2 with cortical malformations (MCPH2; 604317), Yu et al. (2010) identified homozygosity for a 193G-A transition in exon 2 of the WDR62 gene, resulting in a val65-to-met (V65M) substitution at a highly conserved residue. The mutation was not identified in 508 control individuals. Two sibs were more severely affected, with severe microcephaly (-9.2 to -9.8 SD), profound psychomotor delay with spastic quadriparesis, and polymicrogyria and open lip schizencephaly on brain MRI. The third patient had microcephaly (-5.3 SD), developmental delay, and simplified gyral pattern on brain MRI. All had relative preservation of the cerebellum and brainstem.
In 3 Arab sibs, born of consanguineous parents, with MCPH2, Nicholas et al. (2010) identified homozygosity for the V65M mutation. The mutation was not identified in 184 Arab control chromosomes. Brain scans of these patients were not available.
In 2 brothers with primary microcephaly-2 with polymicrogyria (MCPH2; 604317), who were born of unrelated parents of northern European descent, Murdock et al. (2011) identified compound heterozygosity for 2 truncating mutations in the WDR62 gene: a 1-bp deletion (2083delA) in exon 17 and a 2-bp deletion (2472_2473delAG; 613583.0013) in exon 23. Both mutations were predicted to cause nonsense-mediated mRNA decay and loss of function. Each unaffected parent was heterozygous for 1 of the mutations. The mutations were identified by exome sequencing. The phenotype of the sibs varied. The first sib, whose pregnancy was complicated by gestational diabetes, had a more severe phenotype, with extensive bilateral polymicrogyria, abnormal corpus callosum, global developmental delay, intractable seizures, and spastic quadriparesis. The second sib had extensive polymicrogyria and gray matter heterotopia, but did not have seizures; he had age-appropriate cognition and only mild unilateral hemiparesis. Both patients had head circumferences less than the fifth percentile.
For discussion of the 2-bp deletion in the WDR62 gene (2472_2473delAG) that was found in compound heterozygous state in 2 brothers with primary microcephaly-2 with polymicrogyria (MCPH2; 604317) by Murdock et al. (2011), see 613583.0012.
Bhat, V., Girimaji, S., Mohan, G., Arvinda, H., Singhmar, P., Duvvari, M., Kumar, A. Mutations in WDR62, encoding a centrosomal and nuclear protein, in Indian primary microcephaly families with cortical malformations. Clin. Genet. 80: 532-540, 2011. [PubMed: 21496009] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01686.x]
Bilguvar, K., Ozturk, A. K., Louvi, A., Kwan, K. Y., Choi, M., Tatli, B., Yalnizoglu, D., Tuysuz, B., Caglayan, A. O., Gokben, S., Kaymakcalan, H., Barak, T., and 21 others. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467: 207-210, 2010. [PubMed: 20729831] [Full Text: https://doi.org/10.1038/nature09327]
Murdock, D. R., Clark, G. D., Bainbridge, M. N., Newsham, I., Wu, Y.-Q., Muzny, D. M., Cheung, S. W., Gibbs, R. A., Ramocki, M. B. Whole-exome sequencing identifies compound heterozygous mutations in WDR62 in siblings with recurrent polymicrogyria. Am. J. Med. Genet. 155A: 2071-2077, 2011. [PubMed: 21834044] [Full Text: https://doi.org/10.1002/ajmg.a.34165]
Nicholas, A. K., Khurshid, M., Desir, J., Carvalho, O. P., Cox, J. J., Thornton, G., Kausar, R., Ansar, M., Ahmad, W., Verloes, A., Passemard, S., Misson, J.-P., Lindsay, S., Gergely, F., Dobyns, W. B., Roberts, E., Abramowicz, M., Woods, C. G. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nature Genet. 42: 1010-1014, 2010. [PubMed: 20890279] [Full Text: https://doi.org/10.1038/ng.682]
Roberts, E., Jackson, A. P., Carradice, A. C., Deeble, V. J., Mannan, J., Rashid, Y., Jafri, H., McHale, D. P., Markham, A. F., Lench, N. J., Woods, C. G. The second locus for autosomal recessive primary microcephaly (MCPH2) maps to chromosome 19q13.1-13.2. Europ. J. Hum. Genet. 7: 815-820, 1999. [PubMed: 10573015] [Full Text: https://doi.org/10.1038/sj.ejhg.5200385]
Sgourdou, P., Mishra-Gorur, K., Saotome, I., Henagariu, O., Tuysuz, B., Campos, C., Ishigame, K., Giannikou, K., Quon, J. L., Sestan, N., Caglayan, A. O., Gunel, M., Louvi, A. Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly. Sci. Rep. 7: 43708, 2017. Note: Electronic Article. [PubMed: 28272472] [Full Text: https://doi.org/10.1038/srep43708]
Shohayeb, B., Ho, U., Yeap, Y. Y., Parton, R. G., Millard, S. S., Xu, Z., Piper, M., Ng, D. C. H. The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development. Hum. Molec. Genet. 29: 248-263, 2020. [PubMed: 31816041] [Full Text: https://doi.org/10.1093/hmg/ddz281]
Yu, T. W., Mochida, G. H., Tischfield, D. J., Sgaier, S. K., Flores-Sarnat, L., Sergi, C. M., Topcu, M., McDonald, M. T., Barry, B. J., Felie, J. M., Sunu, C., Dobyns, W. B., Folkerth, R. D., Barkovich, A. J., Walsh, C. A. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nature Genet. 42: 1015-1020, 2010. [PubMed: 20890278] [Full Text: https://doi.org/10.1038/ng.683]
Zhou, Y., Qin, Y., Qin, Y., Xu, B., Guo, T., Ke, H., Chen, M., Zhang, L., Han, F., Li, Y., Chen, M., Behrens, A., Wang, Y., Xu, Z., Chen, Z.-J., Gao, F. Wdr62 is involved in female meiotic initiation via activating JNK signaling and associated POI in humans. PLoS Genet. 14: e1007463, 2018. Note: Electronic Article. Erratum: PLoS Genet. 15: e1008504, 2019. [PubMed: 30102701] [Full Text: https://doi.org/10.1371/journal.pgen.1007463]