Alternative titles; symbols
HGNC Approved Gene Symbol: POU1F1
Cytogenetic location: 3p11.2 Genomic coordinates (GRCh38): 3:87,259,404-87,276,584 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p11.2 | Pituitary hormone deficiency, combined or isolated, 1 | 613038 | Autosomal dominant; Autosomal recessive | 3 |
PIT1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals and is a member of the POU family of transcription factors that regulate mammalian development. The POU family is so named because the first 3 members identified were PIT1 and OCT1 (164175) of mammals, and Unc-86 of C. elegans (Herr et al., 1988). PIT1 contains 2 protein domains, termed POU-specific and POU-homeo, which are both necessary for high-affinity DNA binding on genes encoding growth hormone (GH; 139250) and prolactin (PRL; 176760). PIT1 is also important for regulation of the genes encoding prolactin and thyroid-stimulating hormone beta subunit (TSHB; 188540) by thyrotropin-releasing hormone (TRH; 613879) and cyclic AMP.
Bodner et al. (1988) isolated cDNA clones for bovine and rat GHF1 cDNA clones. These cDNAs were found to encode proteins whose molecular mass of 33,000 is identical to purified protein and whose sequence agrees with a partial GHF1 peptide sequence. Near its C terminus, the predicted GHF1 sequence contains a region with considerable similarity to a homeobox consensus sequence. This region of the protein appears to function as its DNA binding domain. Expression of GHF1 was restricted to cells of the somatotropic lineage in the pituitary. The fact that the GHF1 protein contains a homeobox indicates that it is a member of the large family of DNA-binding proteins that control development and differentiation.
The Pit1 gene is located on mouse chromosome 16 in a region between a centromeric segment homologous to human chromosome 3 and a telomeric segment homologous to human chromosome 21 (Camper et al., 1990). Ohta et al. (1992) localized the human PIT1 gene to 3p11 by fluorescence in situ hybridization.
Castrillo et al. (1989) purified GHF1 from extracts of growth hormone and prolactin-expressing pituitary tumor cells. Although GHF1 bound to and activated the growth hormone promoter, it did not recognize the prolactin promoter. In the same extracts, however, at least 1 other factor, which was easily separated from GHF1, bound to several sites within the prolactin promoter but not the growth hormone promoter. Antibodies to GHF1 did not react with the prolactin binding activity. These results indicated that the pituitary-specific expression of these 2 hormones is governed by 2 distinct trans-acting factors.
Ingraham et al. (1988) found that DNA complementary to PIT1 mRNA encodes a 33-kD protein with significant similarity at its C terminus to the homeodomains encoded by Drosophila developmental genes. Ingraham et al. (1988) concluded that PIT1 mRNA is expressed exclusively in the anterior pituitary gland in both somatotroph and lactotroph cell types, which produce growth hormone and prolactin, respectively.
Delhase et al. (1995) showed that use of an alternative splice acceptor site in intron 1 of the human GHF1/PIT1 gene can give rise to a 78-bp in-frame insertion upstream of exon 2 to produce a GHF2/PIT2 cDNA detected in normal human pituitary.
Schanke et al. (1997) examined the expression of Pit1 mRNA splice variants in rhesus pituitary and in rhesus and human placentas. Full-length cDNAs representing Pit1 and the Pit1-beta splice variants were cloned from a rhesus monkey pituitary cDNA library and were detected by RT-PCR with rhesus pituitary gland RNA. Nested RT-PCR was used to detect Pit1 and Pit1-beta variants in both human and rhesus placentas. They concluded that Pit1 splice variants expressed in the rhesus pituitary gland differ from those found in the rodent gland and that the Pit1 and Pit1-beta mRNA isoforms expressed in the placenta give rise to a pattern of protein expression similar to that seen in pituitary cells, which is inducible by treatment with 8-Br-cAMP.
Rajas et al. (1998) characterized 12 kb of genomic DNA upstream of the PIT1 promoter. They identified a distal region that decreases the basal transcriptional activity of the PIT1 minimal promoter, indicating that this region behaves as a silencer. Rajas et al. (1998) found that this distal regulatory region contains 3 PIT1 autoregulatory elements and 2 NF1 (NFIC; 600729)-binding sites. They concluded that NF1 or NF1-related proteins participate in the downregulation of PIT1 gene expression by interacting with an NF1-binding site within the distal region.
Reciprocal gene activation and restriction during cell type differentiation from a common lineage is a hallmark of mammalian organogenesis. A key question is whether a critical transcriptional activator of cell type-specific gene targets can also restrict expression of the same genes in other cell types. Scully et al. (2000) showed that whereas PIT1 activates growth hormone gene expression in one cell type, the somatotrope, it restricts its expression from another cell type, the lactotrope. This distinction depends on a 2-basepair spacing in accommodation of the bipartite POU domains on a conserved growth hormone promoter site. The allosteric effect on PIT1, in combination with other DNA-binding factors, results in the recruitment of a corepressor complex, including the nuclear receptor corepressor (NCOR; 600849), which, unexpectedly, is required for active long-term repression of the growth hormone gene in lactotropes.
PIT1 is involved in 2 functions in the pituitary: PRL and GH tissue-specific expression and somatolactotroph cells expansion. To analyze the molecular basis of the latter function, Gaiddon et al. (1999) tested if PIT1 can directly transactivate expression of an early marker of cell cycle initiation, the c-fos (FOS; 164810). They showed that PIT1 overexpression in PC12 cells, which do not express PIT1, increases FOS expression. They further showed, by gel shift analyses, that PIT1 is able to specifically bind the serum response element sequence present within the FOS promoter but with a lesser affinity than the PIT response element. The authors concluded that the tissue-specific transcription factor PIT1 is able to enhance expression of genes involved in cell cycle initiation, suggesting that this mechanism allows PIT1 to increase somatolactotroph cell proliferation.
Qi et al. (2008) identified 3 highly conserved regulatory elements in the promoter region of the mouse Pit1 gene and found that Atbf1 (ZFHX3; 104155) bound and activated Pit1 from 1 of these elements, EE-alpha. Pituitaries of mice with a hypomorphic Atbf1 allele showed decreased expression of the somatotrope marker, Gh, and almost no expression of the thyrotrope marker, Tshb. Qi et al. (2008) concluded that ATBF1 is required for early PIT1 transcriptional activation.
Skowronska-Krawczyk et al. (2014) found that binding of PIT1-occupied enhancers to a nuclear matrin-3 (MATR3; 164015)-rich network/architecture is a key event in effective activation of the PIT1-regulated enhancer/coding gene transcriptional program. PIT1 association with SATB1 (602075) and beta-catenin (CTNNB; 116806) is required for this tethering event. The R271W mutation (173110.0002) results in loss of PIT1 association with beta-catenin and SATB1 and therefore the matrin-3-rich network, blocking PIT1-dependent enhancer/coding target gene activation. This defective activation could be rescued by artificial tethering of the mutant R271W PIT1 protein to the matrin-3 network, bypassing the prerequisite association with beta-catenin and SATB1. The matrin-3 network-tethered R271W PIT1 mutant, but not the untethered protein, restores PIT1-dependent activation of the enhancers and recruitment of coactivators, exemplified by p300 (EP300; 602700), causing both enhancer RNA transcription and target gene activation. Skowronska-Krawczyk et al. (2014) concluded that these studies revealed an unanticipated homeodomain factor/beta-catenin/SATB1-dependent localization of target gene regulatory enhancer regions to a subnuclear architectural structure that serves as an underlying mechanism by which an enhancer-bound homeodomain factor effectively activates developmental gene transcriptional programs.
Combined or Isolated Pituitary Hormone Deficiency 1
Combined or isolated pituitary hormone deficiency (CPHD1; 613038), involving growth hormone (GH; 139250), prolactin (PRL; 176760), and thyroid-stimulating hormone (TSH; see 188540), is caused by heterogeneous POU1F1 mutations. These include homozygosity or compound heterozygosity for inactivating POU1F1 mutations or heterozygosity for dominant-negative POU1F1 mutations.
Tatsumi et al. (1992) analyzed the PIT1 gene in a female patient with CPHD and identified homozygosity for a nonsense mutation (173110.0001) that was found in heterozygosity in her unaffected consanguineous parents. The authors stated that this was the first description in humans of a defect in a transcription activator causing deficiency of multiple target genes.
In a patient with CPHD, previously reported by Rogol and Kahn (1976), Radovick et al. (1992) identified a heterozygous missense mutation in the PIT1 gene (173110.0002) that was not found in the unaffected mother. Functional analysis demonstrated that the mutant protein bound DNA normally, but acted as a dominant inhibitor of the action of the gene in the pituitary.
In 3 unrelated Japanese children with CPHD, Ohta et al. (1992) identified 2 different missense mutations in heterozygous state in the PIT1 gene (173110.0002 and 173110.0004, respectively) and 1 in homozygous state (173110.0005). Comparison of these 3 mutations and previously reported mutations suggested that mutant PIT1 proteins act as dominant-negative mutants or recessive mutants depending on the location of the mutation, and as a result, hormonal kinetics and the formation of the anterior pituitary are affected.
Pfaffle et al. (1992) analyzed the PIT1 gene in 2 unrelated Dutch families segregating apparently autosomal recessive CPHD, previously reported by Wit et al. (1989), and identified a homozygous missense mutation in the PIT1 gene (A158P; 173110.0003) in affected members of family II, whereas affected members of family I were compound heterozygous for A158P and a maternally inherited deletion of the PIT1 gene.
In a Japanese girl with CPHD involving PRL, GH, and TSH, Okamoto et al. (1994) identified heterozygosity for the R271W mutation in the PIT1 gene. Her unaffected father and paternal grandmother and 2 aunts also carried the mutation. RT-PCR analysis in peripheral lymphocytes revealed monoallelic expression of the normal allele in the father and grandmother and a skewed pattern of biallelic expression in the proband, suggesting epigenetic control of expression of the PIT1 gene.
In a patient with combined deficiency of TSH, GH, and PRL, Irie et al. (1995) identified homozygosity for a nonsense mutation in the POU1F1 gene (173110.0006); the unaffected parents were heterozygous for the mutation.
In 4 sibs with CPHD, born of unaffected consanguineous parents, Pelligrini-Bouiller et al. (1996) identified homozygosity for a missense mutation in the PIT1 gene (F135C; 173110.0007); their mother was heterozygous for the mutation. Vallette-Kasic et al. (2001) analyzed the functional effects of the F135C mutation and demonstrated that the mutant had decreased transactivation capacity on the PRL, GH, and PIT1 genes; structural modeling indicated that interaction with other transcription factors might be prevented.
Aarskog et al. (1997) reported a Norwegian patient with the R271W mutation and found reports of 9 other cases in different populations, suggesting that codon 271 in exon 6 is a hotspot for PIT1 mutations.
Pernasetti et al. (1998) analyzed the PIT1 gene in 3 reportedly unrelated consanguineous Saudi Arabian families with CPHD and identified homozygosity for a missense mutation (P239S; 173110.0008) in all 7 affected children; the unaffected parents were heterozygous for P239S.
In a 4.5-month-old boy who presented with severe congenital hypothyroidism and was subsequently found to have undetectable PRL and GH and a hypoplastic anterior pituitary by MRI, Hendriks-Stegeman et al. (2001) analyzed the POU1F1 gene and identified compound heterozygosity for a 1-bp deletion and a missense mutation (173110.0009 and 173110.0010, respectively). The phenotypically normal parents were heterozygous for the mutations, respectively. Hendriks-Stegeman et al. (2001) stated that the majority of patients with a POU1F1 defect present with growth failure, whereas less than half present with hypothyroidism as the first clinical manifestation. They noted that this was the first frameshift mutation described in the POU1F1 gene to date.
In a 15-year-old Italian girl who had severe growth failure and CPHD, Hashimoto et al. (2003) identified homozygosity for a nonsense mutation in the POU1F1 gene (K145X; 173110.0011). Her parents, who were heterozygous for the mutation, showed evidence of mild endocrine dysfunction. The authors concluded that 2 normal copies of the POU1F1 gene appear necessary for full POU1F1 gene function.
Turton et al. (2005) identified mutations in the POU1F1 gene in 10 (7.8%) of 129 individuals with CPHD. Of these, 5 had the dominant-negative R271W mutation (173110.0002), which is a well-recognized mutation hotspot. The authors identified a second frequently occurring mutation, E230K (173110.0012), which appeared to be common in Maltese patients, and also described 2 novel mutations in POU1F1 (173110.0013 and 173110.0014). Citing the family described by Pelligrini-Bouiller et al. (1996) (see 173110.0007), in which there was variable age of onset of TSH deficiency, as well as their own patient (see 173110.0012) who had a normal T4 at age 20.5 years without thyroid replacement therapy, Turton et al. (2005) suggested that the phenotype associated with POU1F1 mutations may be variable, with the occasional preservation of TSH secretion.
POU1F1 undergoes an evolutionarily conserved program of alternative splicing, resulting in a predominant alpha isoform that acts as a transcriptional activator, and a minor (1 to 3% of transcripts) beta isoform that acts as a transcriptional repressor, created by utilization of an alternative splice acceptor sequence in exon 2. By whole-exome or Sanger sequencing in 4 families with hypopituitarism from European and South American cohorts, Gergics et al. (2021) identified heterozygous variants in the POUF1 gene, clustered in 4 consecutive codons within the beta isoform: S50A (173110.0016), I51S (173110.0017), L52W (173110.0018), and S53A (173110.0019). Functional analysis revealed that although the missense variants retain repressor activity, all 4 shift splicing to favor the expression of the beta isoform almost exclusively, resulting in dominant-negative loss of function. Using saturation mutagenesis coupled to a high-throughput RNA-seq splicing readout, the authors systematically tested possible single-nucleotide variants in or near POU1F1 exon 2, and identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, they identified 2 additional families with hypopituitarism and heterozygous synonymous variants in POU1F1 that were known to disrupt splicing: S50S (173110.0020) in an Argentinian family and I51I (173110.0021) in a French family.
Acquired Combined Pituitary Hormone Deficiency
Yamamoto et al. (2011) reported 3 unrelated men who presented with low serum TSH and free T4, indicating secondary hypothyroidism, as well as undetectable basal levels of GH and PRL. The patients had normal height and adult onset of symptoms, and they were negative for mutation in the PIT1, PROP1 (601538), or HESX1 (601802) genes. All 3 were found to have circulating anti-PIT1 antibodies, as well as various autoantibodies such as those against microsomes, thyroglobulins, thyroid peroxidase (TPO; 606765), GAD (605363), and parietal cells. ELISA-based analysis demonstrated that the anti-PIT1 antibody was highly specific to the disease and absent in controls. Immunohistochemical analysis of the pituitary in 1 patient who died revealed the absence of PIT1-, GH-, PRL-, and TSH-positive cells. Yamamoto et al. (2011) concluded that this represented a new autoimmune polyendocrine syndrome (APS)-related disorder and designated it 'anti-PIT1 antibody syndrome.'
Using an intersubspecific backcross, Camper et al. (1990) demonstrated tight linkage of the Pit1 and Snell dwarf (dw) genes on mouse chromosome 16. Southern blot analysis of genomic DNA showed that the Pit1 gene is rearranged in dwarf mice but not in coisogenic plus/plus animals, providing molecular evidence that a lesion in the Pit1 gene results in the Snell dwarf phenotype. Li et al. (1990) presented evidence that Pit1 is necessary for the specification of the anterior pituitary cell types that produce growth hormone, prolactin, and thyroid-stimulating hormone. They found altered RFLP patterns in the dwarf Jackson mutant, dw(J), as compared with its wildtype strain. The data were considered consistent with a mutational event that resulted in either an inversion or an insertion of a DNA segment of more than 4 kb in the Pit1 gene. The dw(J) mutation is allelic to the dw mutation. Reasoning that the Snell dwarf might represent a point mutation, Li et al. (1990) did studies that demonstrated a G-to-T change that converted the tryptophan residue in the POU-homeodomain (trp261) to cysteine. Neither mRNA nor protein was detected in either of the 2 types of dwarf mice. They also demonstrated that the Ames dwarf (df), a nonallelic mutation that maps to mouse chromosome 11, is associated with absence of detectable Pit1 gene expression. Thus, the Ames mutation appears to be epistatic to the Pit1 locus. The Ames dwarf locus may be involved in the regulation of Pit1, or perhaps in conjunction with Pit1, in the specification and/or maintenance of the 3 specific pituitary cell types affected by the mutation. Andersen et al. (1995) pointed out that the Ames dwarf (df) exhibits a phenotype identical to that of the Pit1-mutated mice. Their studies indicated that initial activation of the Pit1 gene is deficient in the Ames dwarf. This suggested that the df gene is required for activation of the Pit1 gene.
Using transgenic mice expressing the PIT1 and/or GATA-binding protein-2 (GATA2; 137295) genes, Dasen et al. (1999) demonstrated that the appearance of 4 ventral pituitary cell types is mediated via the reciprocal interactions of these 2 transcription factors, which are epistatic to the remainder of the cell type-specific transcription programs and serve as the molecular memory of the transient signaling events. This program includes a DNA binding-independent function of PIT1, suppressing the ventral GATA2-dependent gonadotrope program by inhibiting GATA2 binding to gonadotrope- but not thyrotrope-specific genes, indicating that both DNA binding-dependent and -independent actions of abundant determining factors contribute to the generation of distinct cell phenotypes.
Flurkey et al. (2001) found that mice homozygous for loss-of-function mutations at the Pit1 locus (Snell dwarf) show a more than 40% increase in mean and maximal longevity on a relatively long-lived F1 background. Homozygous animals showed delays in age-dependent collagen cross-linking and in 6 age-sensitive indices of immune system status. These findings thus demonstrated that a single gene can control life span and the timing of both cellular and extracellular senescence in a mammal. Pituitary transplantation into Snell mice did not reverse the life span effect, suggesting that the effect is not due to lowered prolactin levels. In contrast, homozygosity for the 'lit' mutation of the growth hormone release hormone receptor gene (GHRHR; 139191), which, like the Snell dwarf mutation, lowers plasma growth hormone levels, does lead to a significant increase in longevity. Male Snell dwarf mice, unlike calorically restricted mice, become obese and exhibit proportionately high leptin levels in old age, showing that their exceptional longevity is not simply due to alterations in adiposity per se.
The possibility of a mutation in the human equivalent of the Pit1 or df locus as the cause of CPHD in the Hutterite dwarfs pictured by McKusick and Rimoin (1967) and studied by McArthur et al. (1985) was considered (see 262600); however, the disorder in this family has been shown to be caused by defects in the PROP1 gene (see 601538).
In 1 of 2 sisters born to consanguineous parents, who had cretinism due to combined deficiency of thyrotropin, growth hormone, and prolactin (CPHD1; 613038), Tatsumi et al. (1992) demonstrated homozygosity for a nonsense mutation, arg172-to-ter (R172X), in the PIT1 gene. The unaffected parents, who were second cousins, were both heterozygous. The mutant gene resulted in synthesis of a truncated peptide lacking the entire POU-homeo region, where the amino acid sequences of the human and rat peptides are highly conserved. The authors stated that this was the first description in humans of a defect in a transcription activator causing deficiency of multiple target genes.
Radovick et al. (1992) identified a C-to-T transition in codon 271 in approximately one-half of clones of the PIT1 gene from a patient with deficiency of growth hormone, prolactin, and TSH (CPHD1; 613038), which was manifest as severe mental retardation and short stature (Rogol and Kahn, 1976). The patient appeared to have a de novo mutation. Radovick et al. (1992) demonstrated that the mutant gene product bound DNA normally but acted as a dominant inhibitor of the action of the gene in the pituitary. This is, then, an example of dominant-negative mutation. In a Japanese child with combined pituitary hormone deficiency, Ohta et al. (1992) found the same mutation in heterozygous state.
Okamoto et al. (1994) likewise reported a Japanese patient heterozygous for the arg271-to-trp mutation who showed typical clinical features, presumably as the result of a dominant-negative effect. However, her father, grandmother, and 2 aunts had the same mutation without clinical symptoms. By RT-PCR, Okamoto et al. (1994) analyzed the PIT1 transcript in peripheral lymphocytes and found monoallelic expression of the normal allele in the father and grandmother and skewed pattern of biallelic expression in the proband. Thus, there appears to be an epigenetic control on the expression of the PIT1 gene. One explanation for the monoallelic expression is genomic imprinting. Possibly the mutant PIT1 gene silent in the grandmother and the father was reactivated through spermatogenesis in the father, and thus manifested in the granddaughter with a dominant-negative effect.
In a mother and daughter with combined pituitary hormone deficiency, de Zegher et al. (1995) identified heterozygosity for the R271W mutation in the PIT1 gene. At birth, serum T4 was undetectable in mother and infant, and the newborn presented with a striking delay of respiratory, cardiovascular, neurological, and bone maturation. De Zegher et al. (1995) concluded that thyroid hormone is a potent endogenous driver of fetal maturation and that under ordinary circumstances, placental transfer of maternal T4 is a rescue mechanism for infants with congenital hypothyroidism, preventing fetal and neonatal symptoms of thyroid deficiency and safeguarding developmental potential.
Aarskog et al. (1997) reported a Norwegian patient who was heterozygous for the R271W mutation and found reports of 9 other cases in different populations, suggesting that codon 271 in exon 6 is a hotspot for PIT1 mutations. Their patient was a 3-month-old girl with severe growth deficiency from birth as well as distinctive facial features with prominent forehead, marked midfacial hypoplasia with depressed nasal bridge, deep-set eyes, and a short nose with anteverted nostrils. MRI examination showed a hypoplastic pituitary gland. Aarskog et al. (1997) designed a specific amplification-created restriction site assay for the R271W mutation.
Martineli et al. (1998) described the case of a 38-year-old woman, born to consanguineous parents, presenting with growth failure and hypothyroidism. Growth failure was noted in early infancy, whereas hypothyroidism had been apparent only from adolescence. She had almost undetectable growth hormone and prolactin levels and an inappropriately low TSH, while the remaining pituitary evaluation was normal. The pituitary gland was hypoplastic by magnetic resonance imaging. The point mutation in exon 6, present in homozygous form, was a C-to-T substitution that changed amino acid 271 from arg to trp.
In 5 patients with CPHD, including a mother and daughter and an unrelated mother and son with CPHD, Turton et al. (2005) identified heterozygosity for the R271W mutation in the POU1F1 gene. Noting that Okamoto et al. (1994) had suggested that the R271W mutation might be variably penetrant, possibly because of monoallelic expression, Turton et al. (2005) stated that their data and those of de Zegher et al. (1995) did not support that hypothesis.
In 2 unrelated Dutch families, each with 2 affected and 3 unaffected sibs with combined pituitary hormone deficiency (CPHD1; 613038) inherited presumably as an autosomal recessive (Wit et al., 1989), Pfaffle et al. (1992) identified a C-G transversion in exon 4 of the POU1F1 gene, resulting in an ala158-to-pro (A158P) substitution. The affected sibs in 1 family were thought to be compound heterozygotes for the A158P allele inherited from the father and a PIT1 deletion allele inherited from the mother; the 2 affected sibs in the other family were homozygous for the A158P mutation. In the mother's line, the entire coding sequence of the PIT1 gene was deleted. The A158P mutation was in the first putative alpha-helix of the POU-specific domain and generated a protein capable of binding to DNA response elements but unable to activate effectively its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggested that the mutant protein is competent in initiating other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, the mutation in the POU-specific domain of PIT1 had a selective effect on a subset of PIT1 target genes.
In a Japanese child with combined pituitary hormone deficiency (CPHD1; 613038), Ohta et al. (1992) identified heterozygosity for a C-T transition in the POU1F1 gene, resulting in a pro24-to-leu (P24L) substitution at a highly conserved residue in the major transactivation region. The authors stated that the mutant gene product may bind DNA normally but act as a dominant inhibitor of PIT1 action.
The arg143-to-gln mutation found by Ohta et al. (1992) in a Japanese child with combined pituitary hormone deficiency (CPHD1; 613038) resulted from a G-to-A transition, which was predicted to encode a CGA-to-CAA substitution. The patient was homozygous for the mutation; both parents and 2 sibs were heterozygous. The mutation occurred in the POU-specific domain which is important for DNA binding. Thus, mutations in the PIT1 gene may result in a dominant or a recessive phenotype depending on the part of the gene product molecule that is affected.
In a patient with combined deficiency of TSH, GH, and PRL (CPHD1; 613038), Irie et al. (1995) found substitution of glutamate-250 by a termination codon (E250X) in homozygous state. Both of the healthy parents harbored this mutation in the heterozygous state. The mutation resulted in complete loss of helix 3 of the POU homeodomain of the gene product. As helix 3 of the homeodomain is involved directly in DNA binding, the mutant protein may lose this capacity and thus lose its transcriptional activation.
In 4 sibs with combined pituitary hormone deficiency (CPHD1; 613038), born of unaffected consanguineous parents, Pelligrini-Bouiller et al. (1996) identified homozygosity for a T-G transversion in the POU1F1 gene, predicted to result in a phe135-to-cys (F135C) substitution at a conserved residue within the hydrophobic core of the POU-specific DNA-binding domain of the Pit1 protein. Their mother was heterozygous for the mutation, suggesting autosomal recessive inheritance.
Vallette-Kasic et al. (2001) studied the functional effect of the F135C mutation. In vitro activity tests performed by transfection in human HeLa cells showed decreased transactivation capacity on the PRL, GH, and PIT1 genes. The DNA binding experiments performed by gel shift showed that the F135C mutation generated a protein capable of binding to DNA response elements. To analyze how the F135C mutation might affect functionality of the transcription factor despite a normal DNA binding, they used a structure modelization approach. According to structural data derived from the crystallographic analysis of the DNA/PIT1 POU domain complex, the conformation of the first helix of the F135C-mutated POU-specific domain could be perturbed to such an extent that any interaction with other transcription cofactors might be prevented.
In 7 children with combined pituitary hormone deficiency (CPHD1; 613038) from 3 reportedly unrelated consanguineous Saudi Arabian families, Pernasetti et al. (1998) identified homozygosity for a T-C transition in exon 6 of the POU1F1 gene, resulting in a pro239-to-ser (P239S) substitution at a highly conserved residue at the beginning of the second alpha-helix of the POU homeodomain. The unaffected parents were heterozygous for the mutation. Functional studies demonstrated that the mutant binds DNA normally but is unable to stimulate transcription.
In a 4.5-month-old boy who presented with severe congenital hypothyroidism and was subsequently found to have undetectable PRL and GH and a hypoplastic anterior pituitary by MRI (CPHD1; 613038), Hendriks-Stegeman et al. (2001) identified compound heterozygosity for 2 novel point mutations in the POU1F1 gene: a 1-bp deletion (747delA), causing a frameshift resulting in a nonfunctional truncated protein lacking the entire DNA recognition helix of the POU homeodomain, and a 577T-C transition in exon 4, resulting in a trp193-to-arg (W193R; 173110.0010) substitution in the C-terminal end of the fourth alpha-helix of the POU-specific domain, which causes a 500-fold reduction in the ability to bind to DNA and activate transcription.
For discussion of the trp193-to-arg (W193R) mutation in the POU1F1 gene that was found in compound heterozygous state in a patient with severe congenital hypothyroidism (CPHD1; 613038) by Hendriks-Stegeman et al. (2001), see 173110.0009.
In a 15-year-old Italian girl with severe growth failure and combined pituitary hormone deficiency (CPHD1; 613038), Hashimoto et al. (2003) identified homozygosity for an A-T transversion in the POU1F1 gene, resulting in a lys145-to-ter (K145X) substitution in the 3-prime end of the first alpha-helix of the POU-specific domain and generating a truncated protein with loss of most of the PIT1 DNA-binding domains. Her nonconsanguineous parents, who each had 1 mutant allele, showed evidence of mild endocrine dysfunction. Hashimoto et al. (2003) concluded that 2 normal copies of the POU1F1 gene appear necessary for full POU1F1 gene function.
In 4 patients from Malta and 1 from Russia with combined pituitary hormone deficiency (CPHD1; 613038), Turton et al. (2005) identified a 688G-A transition in exon 6 of the POU1F1 gene that resulted in substitution of a glutamate residue by lysine at position 230 (E230K) in the first alpha-helix of the POU-H. Two patients (Maltese sibs) were compound heterozygous for this mutation and a missense mutation at codon 172 (173110.0013); the Russian patient was compound heterozygous for this mutation and a 1-basepair insertion (173110.0014). The other 2 patients, sibs from a consanguineous Maltese family, were homozygous for the E230K mutation. One of these patients had preserved T4 secretion. Functional studies showed that the E230K mutation is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wildtype protein. This mutation had been described by Gat-Yablonski et al. (2002) in 2 sibs from a consanguineous Israeli-Arab pedigree.
In 2 Maltese sibs with combined pituitary hormone deficiency (CPHD1; 613038), Turton et al. (2005) identified a novel 515G-A transition within exon 4 of the POU1F1 gene that resulted in substitution of arginine by glutamine at codon 172 in the POU-S (R172Q). These patients were compound heterozygous for this mutation and E230K (172110.0012). Functional studies revealed that the R172Q mutation is associated with a reduction in DNA binding and transactivation.
In a Russian patient with combined pituitary hormone deficiency (CPHD1; 613038), Turton et al. (2005) identified novel insertion of an adenine at position 778 in exon 6 of the POU1F1 gene (778insA). This insertion was predicted to result in frameshift with a truncated protein of 284 amino acids. The patient was compound heterozygous for the insertion and an E230K substitution (172110.0012). Functional studies revealed that the ins778A mutation is associated with loss of DNA binding and a reduction in transactivation.
In a 20-year-old Japanese man with combined pituitary hormone deficiency (CPHD1; 613038), Miyata et al. (2006) identified a homozygous C-to-G transversion in exon 4 of the POU1F1 gene that resulted in a ser179-to-arg (S179R) substitution. Transfection studies in POU1F1-deficient cells showed that the transactivation capacity of this mutant was markedly decreased on the GH1 (139250), PRL (176760), TSH-beta (188540), and POU1F1 genes. Interestingly, this mutation abolished the functional interaction of POU1F1 on the PRL promoter with the coactivator cAMP response element-binding protein-binding protein (CREBBP; 600140) but not with the transcription factor LIM homeodomain transcription factor-3 (LHX3; 600577). The S179R mutant displayed normal nuclear accumulation but a markedly decreased binding to a DNA response element.
In a brother and sister (family 1) with combined pituitary hormone deficiency (CPHD1; 613038), Gergics et al. (2021) identified heterozygosity for a c.148T-G transversion (c.148T-G, NM_001122757.2) in exon 2 of the POU1F1 gene, resulting in a ser50-to-ala (S50A) substitution at a highly conserved residue within the beta isoform. The variant, which was not found in an in-house population-matched exome database or in the gnomAD database, was inherited from their apparently unaffected mother, indicating incomplete penetrance. RT-PCR in transfected COS7 cells demonstrated that the c.148T-G variant predominantly produced the beta isoform of POU1F1, and functional analysis showed that neither the wildtype POU1F1 beta isoform nor the S50A mutant significantly activated a POUF1F1 reporter.
In 4 patients over 3 generations of a family (family 2) with growth hormone deficiency (CPHD1; 613038), Gergics et al. (2021) identified heterozygosity for a c.152T-G transversion (c.152T-G, NM_001122757.2) in exon 2 of the POU1F1 gene, resulting in an ile51-to-ser (I51S) substitution at a highly conserved residue within the beta isoform. The variant segregated with disease in the family and was not found in an in-house population-matched exome database or in the gnomAD database. RT-PCR in transfected COS7 cells demonstrated that the c.152T-G variant predominantly produced the beta isoform of POU1F1, and functional analysis showed that neither the wildtype POU1F1 beta isoform nor the I51S mutant significantly activated a POUF1F1 reporter.
In a female patient (family 3) with combined pituitary hormone deficiency (CPHD1; 613038), Gergics et al. (2021) identified heterozygosity for a de novo c.155T-G transversion (c.155T-G, NM_001122757.2) in exon 2 of the POU1F1 gene, resulting in a leu52-to-trp (L52W) substitution at a highly conserved residue within the beta isoform. The variant was not found in an in-house population-matched exome database or in the gnomAD database. RT-PCR in transfected COS7 cells demonstrated that the c.155T-G variant predominantly produced the beta isoform of POU1F1, and functional analysis showed that neither the wildtype POU1F1 beta isoform nor the L52W mutant significantly activated a POUF1F1 reporter.
In a mother and daughter (family 4) with combined pituitary hormone deficiency (CPHD1; 613038), Gergics et al. (2021) identified heterozygosity for a c.157T-G transversion (c.157T-G, NM_001122757.2) in exon 2 of the POU1F1 gene, resulting in a ser53-to-ala (S53A) substitution at a highly conserved residue within the beta isoform. The variant segregated with disease in the family and was not found in an in-house population-matched exome database or in the gnomAD database. RT-PCR in transfected COS7 cells demonstrated that the c.157T-G variant predominantly produced the beta isoform of POU1F1, and functional analysis showed that neither the wildtype POU1F1 beta isoform nor the S53A mutant significantly activated a POUF1F1 reporter.
In an Argentinian father and son (family 5) with growth hormone deficiency (CPHD1; 613038), Gergics et al. (2021) identified heterozygosity for a c.150T-G transversion (c.150T-G, NM_001122757.2) in exon 2 of the POU1F1 gene, resulting in a ser50-to-ser (S50S) synonymous substitution. The mutation was not found in an in-house population-matched exome database or in the gnomAD database. The silent variant increased beta isoform usage 10.7-fold compared to wildtype.
In 2 French half-brothers (family 6) with growth hormone deficiency (CPHD1; 613038), Gergics et al. (2021) identified heterozygosity for a c.153T-A transversion (c.153T-A, NM_001122757.2) in exon 2 of the POU1F1 gene, resulting in an ile51-to-ile (I51I) synonymous substitution. The mutation was not found in an in-house population-matched exome database or in the gnomAD database. DNA was unavailable from their mother for segregation analysis; the authors noted that she might be an unaffected carrier, indicating incomplete penetrance, or she might represent an example of gonadal mosaicism. The silent variant increased beta isoform usage 4.15-fold compared to wildtype.
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