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ABSTRACT: The growth hormone (GH)/insulin-like growth factor-1(IGF-1) axis is the key regulator of somatic growth in humans and its genes are plausible candidates to study the genetics of height variation. Here, we studied polymorphic variation in the GH/IGF-1 axis in the extremely tall Dutch.
Case-control study of 166 tall cases with height >2 SDS and 206 controls with normally distributed height <2 SDS. Excluded were subjects with endocrine disorders or growth syndromes. We analyzed genomic DNA at 7 common polymorphisms in the GH-1, GH receptor (GHR), IGF-1 and IGFBP-3 genes.
The association of the GH-1 1663 SNP with tall stature approached statistical significance, with the T-allele more present in the tall (allele frequency (AF): 0.44 vs. 0.36; p=0.084). Moreover, haplotype frequencies at this locus were significantly different between cases and controls, with the GGT haplotype most commonly seen in cases (p=0.01). Allele frequencies of GHR polymorphisms were not different. For the IGF-1 CA-repeat we observed a higher frequency of homozygous 192-bp carriers among tall males compared to control males (AF: 0.62 vs. 0.55; p=0.02). The IGFBP-3 -202 C-allele occurred more frequently in cases than in controls (AF: 0.58 vs. 0.50; p=0.002). Within cases, those carrying one or two copies of the -202 C-allele were significantly taller than AA genotype carriers (AC, p=0.028 and CC, p=0.009). Serum IGFBP-3 levels were highest in AA genotype carriers, the -202 SNP explained 5.8% of the variation.
Polymorphic variation in the GH-1, IGF-1 and IGFBP-3 genes is associated with extremely tall stature. In particular, the IGFBP-3 -202 SNP is associated not only with being very tall but also with height variation within the tall.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 09/2011; 21(6):318-24. · 2.35 Impact Factor
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ABSTRACT: Genetic variation in several candidate genes has been associated with short stature. Recently, a high-mobility group A2 (HMGA2) gene SNP has been robustly associated with height in the general population. Only few have attempted to study these genes in extremely tall stature. We therefore studied common genetic variation in candidate genes for height in extremely tall Dutch.
We included 116 constitutionally tall cases with height >2 SD and 103 controls with normally distributed height <2 SD. We genotyped 10 common polymorphisms previously associated with height variation.
The HMGA2 gene SNP was significantly associated with tall stature. Using a logistic regression model, we calculated that carrying the HMGA2 (rs1042725) C allele significantly increased the odds of being tall (OR = 1.53, 95% CI 1.02-2.28; p = 0.03). In addition, controls with one or two copies of the C allele were significantly taller than controls carrying the TT genotype [TC: mean (SD) +0.61 (0.21) SDS; p = 0.004, and CC: +0.77 (0.25) SDS; p = 0.003].
Our study shows that a common polymorphism in the HMGA2 gene is not only associated with height variation in the general population but also plays an important role in one of the extremes of the height distribution.
Hormone Research in Paediatrics 09/2011; 76(5):307-13.
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ABSTRACT: Pituitary adenomas account for approximately 10% of intracranial tumors, but little is known of the oncogenesis of these tumors. The identification of tumor-specific genes may further elucidate the pathways of tumor formation. We used complementary DNA microarrays to examine gene expression profiles in nonfunctioning, PRL, GH, and ACTH secreting adenomas, compared with normal pituitary. Microarray analysis showed that 128 of 7075 genes examined were differentially expressed. We then analyzed three genes with unique expression patterns and oncogenic importance by RT-real time quantitative PCR in 37 pituitaries. Folate receptor gene was significantly overexpressed in nonfunctioning adenomas but was significantly underexpressed in PRL and GH adenomas, compared with controls and to other tumors. The ornithine decarboxylase gene was significantly overexpressed in GH adenomas, compared with other tumor subtypes but was significantly underexpressed in ACTH adenomas. C-mer proto-oncogene tyrosine kinase gene was significantly overexpressed in ACTH adenomas but was significantly underexpressed in PRL adenomas. We have shown that at least three genes involved in carcinogenesis in other tissues are also aberrantly regulated in the major types of pituitary tumors. The evaluation of candidate genes that emerge from these experiments provides a rational approach to investigate those genes significant in tumorigenesis.
Journal of Clinical Endocrinology & Metabolism 08/2001; 86(7):3097-107. · 6.50 Impact Factor
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ABSTRACT: The molecular pathogenesis of the majority of sporadic pituitary tumors is largely unknown. Pituitary adenomas can develop sporadically or as a part of multiple endocrine neoplasia type 1 (MEN1). The MEN1 is thought to be a tumor suppressor gene based on loss of heterozygosity (LOH) for polymorphic markers on 11q13 in tumors of the pancreas, parathyroid, and pituitary. Most patients with familial and sporadic MEN1 carry germ-line mutations in the MEN1 gene. Two previous studies and recently a third one have analyzed mutations by sequencing the MEN1 gene in sporadic pituitary tumors but yielded conflicting results. This study was to investigate and clarify the potential role of MEN1 mutations, in sporadic pituitary adenomas. First, we examined 59 sporadic pituitary adenomas by analyzing LOH on 11q13 in the MEN1 minimal interval with microsatellite analysis. We found 3 tumors with LOH in 1 to 4 polymorphic markers in the MEN1 region. Sequencing analysis did not reveal any mutations in the coding region of the MEN1 gene. However, we found 3 polymorphisms, one of which was a novel CAC to CAT transition encoding His433His, in exon 9. The data show that while LOH occurs in some sporadic pituitary tumors, inactivating mutations of the tumor suppressor gene MEN1 are rare. These results also suggest there may be another additional tumor suppressor gene at this locus which is involved in the pathogenesis of sporadic pituitary neoplasms.
Journal of endocrinological investigation 06/2000; 23(5):304-9. · 1.57 Impact Factor
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ABSTRACT: We have found a novel mutation in intron 4 of the GH-1 gene in a Bedouin kindred with isolated growth hormone deficiency type IB (IGHD IB). RFLP analysis suggested linkage between the GH-1 gene and IGHD. Nested PCR amplification followed by single stranded conformation polymorphism (SSCP) analysis indicated sequence variation between introns 2 and 4. Sequencing showed a G-->C transversion at the fifth base in the splice donor region of intron 4. Affected individuals were homozygous for the mutation, which creates a new Mae III restriction site. Reverse transcription and PCR of GH-1 transcripts in EBV transformed lymphocytes indicated predominance of a species lacking 73 bp of exon 4. Amplification with a bridging primer showed that the same mRNA species is present in lymphocytes from normal individuals. The first 102 amino acids of the predicted protein are identical to wild-type GH, but the next 94 amino acids are completely divergent.
Journal of pediatric endocrinology & metabolism: JPEM 01/2000; 13(1):21-8. · 0.88 Impact Factor
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ABSTRACT: Isolated growth hormone deficiency (IGHD) IB is an autosomal recessive disorder characterized by a good response to exogenous growth hormone (GH) treatment without development of anti-GH antibodies. Patients with IGHD IB were found to be compound heterozygotes for deletion and frameshift mutations as well as homozygotes for splicing mutations in the GH-1 gene. Recently, a novel splicing mutation in the GH-1 gene was identified in an extended, consanguineous Arab-Bedouin family from Israel with IGHD IB. Prior to the identification of this mutation, a considerable number of children with short stature in this family were found normal on pharmacological stimulation for GH release. This observation prompted a genotype/phenotype correlation of potential heterozygotes in the family. Carriers of the mutant GH-1 allele were found as a group to have a significantly shorter stature than normal homozygote (mean standard deviation scores, 1.67 and -0.40, respectively, P<0.05). Moreover, 11 of 33 (33%) heterozygotes, but only 1 of 17 (5.9%) normal homozygotes, had their height at 2 or more SD below the mean. Overall, 48.5% of studied heterozygotes were found to be of appreciably short stature with height at or lower than the 5th centile (> or = -1.7 SD), whereas only 5.9% of the normal homozygotes did (P<0.004). This phenomenon of heterozygotes for a recessive mutation in the GH-1 gene manifesting short stature, might imply that some such mutations may account for non-GH deficiency reduced height in the general population.
American Journal of Medical Genetics 01/2000; 90(3):188-92.
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ABSTRACT: Basic and translational research achievements over the past 2 decades have disclosed the molecular mechanisms underlying several genetic forms of hypopituitarism. Disorders that are limited to the hypothalamic, pituitary, GH axis are caused by mutations in individual components of that axis. Disorders involving GH and one or more additional pituitary hormones are caused by mutations in the homeodomain transcription factors that direct embryological development of the anterior pituitary gland. Pit-1 has a POU-specific and a POU-homeo DNA-binding domain. The phenotype produced by mutations in the PIT1 gene involves deficiencies of GH, PRL, and TSH. Pituitary glands are either small or normally sized. The PROP1 gene encodes a transcription factor with a single paired-like DNA-binding domain. Persons with inactivating mutations in PROP1 have deficiencies of LH and FSH, as well as GH, PRL, and TSH. Their pituitary glands may be small, normally sized, or extremely large and show suprasellar extension. Pituitary degeneration may produce acquired deficiency of ACTH. Expression of the HESX1 gene precedes expression of PROP1 and PIT1, and it is much more widespread. The protein has a paired-like domain, and it competes with the product of PROP1 for DNA-binding. Homozygosity for inactivating mutations of HESX1 produces a complex phenotype that resembles septo-optic dysplasia. Much more needs to be learned about the role of HESX1 mutations in other forms of hypopituitarism.
Journal of Clinical Endocrinology & Metabolism 01/2000; 84(12):4362-70. · 6.50 Impact Factor
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ABSTRACT: This review will address contributions of nuclear transcription factors to the embryologic development and definitive function of the anterior pituitary gland. The HESX1, PITX1, PITX2, PROP1 and POU1F1 genes are of particular interest because of their recognized or potential associations with human disease. Mutations of any of the first three genes produce complex disease phenotypes such as septo-optic dysplasia, Treacher Collins Franceschetti syndrome or Rieger syndrome that may include deficiency of one or more pituitary hormones. Mutations in PROP1 or POU1F1, or their mouse homologous, result in severe hypopituitarism as well as morphological abnormalities of the pituitary gland.
Growth Hormone & IGF Research 07/1999; 9 Suppl B:2-8; discussion 8-11. · 2.16 Impact Factor
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O Fofanova,
N Takamura,
E Kinoshita,
J S Parks, M R Brown,
V A Peterkova,
O V Evgrafov,
N P Goncharov,
A A Bulatov,
I I Dedov,
S Yamashita
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ABSTRACT: Mutations in the prophet of Pit-1 gene (PROP1) have been shown to be responsible for combined pituitary hormone deficiency (CPHD) with deficiencies of growth hormone (GH), Prolactin (Prl), thyroid-stimulating hormone (TSH) and gonadotropins. We previously reported that homozygosity for a 2bp deletion in exon 2 (296delGA) accounted for CPHD in three patients from two Russian families. Here we report a second mutational hot spot in exon 2. This 2bp 149delGA deletion results in a frame shift that leads to the same serine to stop codon change at codon 109 (S109X). The predicted proteins are each truncated at residue 108 but diverge from the wild type sequence at different points in the homeodomain. Compound heterozygosity for the two mutations (149delGA/296delGA) was detected in 5 of 14 CPHD children from 4 families (36%). This provides the first evidence of heterozygosity for two common deletions as a cause of CPHD in Russian children.
Journal of Clinical Endocrinology & Metabolism 08/1998; 83(7):2601-4. · 6.50 Impact Factor
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O V Fofanova,
N Takamura,
E Kinoshita,
J S Parks, M R Brown,
V A Peterkova,
O V Evgrafov,
N P Goncharov,
A A Bulatov,
I I Dedov,
S Yamashita
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ABSTRACT: Combined pituitary hormone deficiency (CPHD), including growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH) in children is now considered a heterogeneous syndrome. Recent findings on expression of mouse pituitary-specific homeodomain factors demonstrate dependence of adenopituitary ontogeny on interactive expression of these factors, suggesting their involvement in etiology of CPHD. Prophet of Pit-1 (Prop-1) gene, a novel pituitary-specific homeodomain factor, was analyzed in 14 Russian children with CPHD, in whom Pit-1 gene was intact. We found a mutational hot spot in three patients from two families in homeodomain part of the second exon of Prop-1 gene. The common 2-base pair deletion (GA296) in the homozygous state resulted in a Serine to Stop codon (S109X) substitution and generated a truncated Prop-1 protein. Parents were phenotypically normal and heterozygous for GA296 deletion, indicating an autosomal recessive inheritance. These results demonstrate a novel type of Prop-1 gene mutation as one of the causes of CPHD in Russian patients.
Pituitary 05/1998; 1(1):45-9. · 1.83 Impact Factor
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W Wu,
J D Cogan,
R W Pfäffle,
J S Dasen,
H Frisch,
S M O'Connell,
S E Flynn, M R Brown,
P E Mullis,
J S Parks,
J A Phillips,
M G Rosenfeld
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ABSTRACT: Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH) and one or more of the other five anterior pituitary hormones. Mutations of the pituitary transcription factor gene POU1F1 (the human homologue of mouse Pit1) are responsible for deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) is preserved. The Ames dwarf (df) mouse displays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Ames dwarf gene Prop1, which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is necessary for Pit1 expression. In this report, we have identified four CPHD families with homozygosity or compound heterozygosity for inactivating mutations of PROP1. These mutations in the human PROP1 gene result in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP1 mutations cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously. Our results identify a major cause of CPHD in humans and suggest a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.
Nature Genetics 03/1998; 18(2):147-9. · 35.53 Impact Factor
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ABSTRACT: Mutations in the gene encoding the Pit-1 transcriptional activator interfere with the embryologic determination and ultimate functions of anterior pituitary cells that produce growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH). Central hypothyroidism is often the presenting feature of combined pituitary hormone deficiency (CPHD), but it is not detected in screening programs that rely upon elevation of TSH. We report a child whose hypothyroidism was recognized clinically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency. With thyroxine and GH replacement he has reached the 70th percentile for height and has normal intelligence. Molecular analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 and a novel missense mutation substituting glycine for glutamate at codon 174. This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations. Therefore, in cases of CPHD, the possibilities of compound heterozygosity for two different Pit-1 mutations, or homozygosity for mutations in the epigenetic gene, Prop-1, should be considered.
Hormone Research 02/1998; 49(2):98-102. · 2.48 Impact Factor
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ABSTRACT: Mutant, guanosine triphosphatase-deficient, alpha-subunits of the G protein, Gs, gsp ocogene have been discovered in 40% of GH-secreting pituitary adenomas. Therefore, we hypothesized that a novel G protein class, G alpha q, involved in pituitary signal transduction, might be involved in pituitary tumorigenesis. Recombinant mutations of G alpha q result in constitutive activation of phospholipase C and have transforming activity. Therefore, we screened tumor samples from 37 pituitary adenomas for the presence of activating mutations of the G alpha q gene. Importantly, our sample contains 8 FSH and LH adenomas. In the pituitary gland, FSH and LH are linked to the GnRH-G alpha q signaling cascade, making these tumors a logical choice for screening for G alpha q mutations. Complementary DNA (cDNA) was synthesized by RT-PCR with G alpha q specific primers to exclude pseudogene transcripts. Fragments of G alpha q cDNA-encompassing residues (Arg183, Gln209) were screened by single-strand conformation polymorphism and then sequenced in both directions. No mutations were detected. We conclude that mutations in these regions of the G alpha q cDNA occur infrequently, if at all, in human pituitary adenomas. Alternative mechanisms underlying pituitary tumorigenesis should be explored.
Journal of Clinical Endocrinology & Metabolism 01/1998; 82(12):4184-8. · 6.50 Impact Factor
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ABSTRACT: Several pituitary transcription factors have been identified in the last 3 years. They offer new insights into the processes that direct organogenesis, cell commitment, proliferation and differentiated function. All are DNA-binding proteins, but they have ties to different families of homeodomain proteins. They differ in their distribution and in the timing of their appearance and extinction. The Rathke's pouch homeobox protein (Rpx) has a paired-like homeodomain. In mice, it appears on embryonic day 8.5 (day e8.5) and is gone by day e14.5. Its targets for activation are unknown. Pituitary OTX has a tryptophan--phenylalanine--lysine motif in its homeodomain. It appears early and persists. It shows independent activation of the alpha-glycoprotein subunit (alpha-GSU) and pro-opiomelanocortin genes and co-operates with Pit-1 in activation of the growth hormone and prolactin genes. Pituitary Lim (P-Lim) protein also acts independently on the alpha-GSU gene, and acts in concert with Pit-1 to activate other genes. A fourth protein, termed the 'Prophet of Pit-1', or Prop-1, is the recently discovered cause of Ames dwarfism in mice. This paired-like protein is necessary for the subsequent expression of Pit-1 in somatotrophs, lactotrophs and thyrotrophs. Any or all of the newly discovered pituitary genes are candidates for mutations causing hypopituitarism in humans. As several are expressed transiently in tissues other than the pituitary during organogenesis, the phenotypes produced by mutations in these genes may prove to be complex.
Acta paediatrica (Oslo, Norway: 1992). Supplement 12/1997; 423:28-32.
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ABSTRACT: To summarize the steps that led to the recognition of the Laron syndrome of growth-hormone (GH) insensitivity as a recessive disorder that is caused by mutations in the growth hormone receptor (GHR) gene, to discuss the different types of mutations that have been found in the GHR gene, and to examine whether the degree of growth impairment in affected homozygotes depends on the specific type of GHR mutation.
A broad spectrum of abnormalities in the GHR gene have been reported. These abnormalities range from deletions of multiple exons, through deletions of a small number of base pairs, nonsense mutations, missense mutations that alter GH-binding affinity or impair receptor processing, to mutations that exert their deleterious effects by altering messenger RNA splicing and result in the loss of portions of the GHR.
Different abnormalities in the GHR gene have different effects on the concentrations of circulating GH-binding protein that represents the extracellular portion of the GHR. Homozygosity or compound heterozygosity for the different mutations produces a fairly uniform phenotype of severe postnatal growth retardation. The differences in height standard deviation scores between persons appear to depend more on age, sex, and nutritional status than on the specific type of GHR mutation.
Journal of Pediatrics 08/1997; 131(1 Pt 2):S45-50. · 4.11 Impact Factor
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ABSTRACT: Noncontiguous deletion of the GH receptor (GHR) gene has been described as a molecular defect causing Laron's syndrome (LS). The abnormal allele (GHR Del-3,5,6) lacks exons 3, 5, and 6. Exon 4 is retained on variant-sized restriction fragments. We studied DNA from 10 additional LS subjects of Jewish-oriental origin and found this allele in 3 samples. All subjects with this complex deletion allele were from Iran or Iraq and were not clinically distinguishable from other individuals with LS. Multiple restriction enzyme digests and Southern blotting with GHR exon 4-specific probes demonstrated that the allele retains genomic material for at least 9.8 kilobases 5' and 1.8 kilobases 3' to exon 4. Reverse transcription of mRNA, polymerase chain reaction amplification, and cDNA sequencing showed that exon 4 is syntenic and colinear with the other GHR exons. Normal splice sites were used, but the predicted protein was severely truncated due to a frameshift and a premature stop codon in exon 7. The premature stop codon terminated the protein after amino acid 53 and led to loss of the transmembrane and intracellular portions of the receptor. This mutant GHR gene results clinically in severe GH insensitivity.
Journal of Clinical Endocrinology & Metabolism 12/1993; 77(5):1379-83. · 6.50 Impact Factor
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ABSTRACT: The regulation of pituitary GH gene expression depends on binding of transcriptional activation proteins to cis-active DNA sequences preceding the GH-1 gene. The POU homeodomain protein Pit-1 is found in the nuclei of somatotrophs, lactotrophs and thyrotrophs. It fosters differentiation of these pituitary cell types and is required for hormone production by mature cells. In theory, defects in GH secretion can be caused by mutations in the GH-1 promoter sequence or in the gene encoding Pit-1. In the former case, deficiency would be limited to GH, and in the latter deficiencies extend to prolactin (Prl) and thyrotropin (TSH) as well as to GH. Both the Pit-1 gene and the GH-1 gene have been examined in children with extreme growth failure. Studies of kindreds with GH, Prl and TSH deficiency have disclosed a variety of mutations in the Pit-1 gene. These include nonsense mutations, missense mutations that diminish binding and transcriptional activation, and also mutations that appear to increase promoter binding while eliminating transcriptional activation. This latter class of mutation exerts a dominant negative effect in vivo as well as in vitro. There are many examples of deletions in the GH-1 coding sequence. Some are very large and cause the loss of GH-1, chorionic somatomammotropin and placental GH genes. Others are very small, involving only 1 or 2 bases. They produce frameshifts and premature stop signals. All types produce complete deficiency of GH, but antibody development during treatment has proven to be quite variable. The cDNA for the GH-releasing hormone receptor has recently been cloned and sequenced.(ABSTRACT TRUNCATED AT 250 WORDS)
Hormone Research 02/1993; 40(1-3):54-61. · 2.48 Impact Factor
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Acta paediatrica (Oslo, Norway: 1992). Supplement 10/1992; 383:73-7; discussion 78.
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ABSTRACT: A point mutation in the POU-specific portion of the human gene that encodes the tissue-specific POU-domain transcription factor, Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative alpha helix of the POU-specific domain to proline was observed. This mutation generated a protein capable of binding to DNA response elements but unable to effectively activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset of Pit-1 target genes.
Science 09/1992; 257(5073):1118-21. · 31.20 Impact Factor
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ABSTRACT: A point mutation in the POU-specific portion of the human gene that encodes the tissuespecific POU-domain transcription factor,
Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two
unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative α helix of the POU-specific domain
to proline was observed. This mutation generated a protein capable of binding to DNA response elments but unable to effectively
activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the
mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope,
lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset
of Pit-1 target genes.
Science 08/1992; 257(5073):1118-1121. · 31.20 Impact Factor
