{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:13:52Z","timestamp":1790910832326,"version":"4.1.0"},"reference-count":40,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,8,1]]},"abstract":"<jats:p>Context: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency.<\/jats:p><jats:p>Objective: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1.<\/jats:p><jats:p>Results: Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation.<\/jats:p><jats:p>Conclusions: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.<\/jats:p>","DOI":"10.1210\/jc.2005-0570","type":"journal-article","created":{"date-parts":[[2005,8,8]],"date-time":"2005-08-08T21:37:43Z","timestamp":1123537063000},"page":"4762-4770","source":"Crossref","is-referenced-by-count":101,"title":["Novel Mutations within the POU1F1 Gene Associated with Variable Combined Pituitary Hormone Deficiency"],"prefix":"10.1210","volume":"90","author":[{"given":"James P. 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Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ray","family":"Parascandalo","sequence":"additional","affiliation":[{"name":"St. Luke\u2019s Hospital (J.T., S.A.-M., R.P., C.V.), Department of Paediatrics, Guardamangia MSD09, Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecil","family":"Vella","sequence":"additional","affiliation":[{"name":"St. Luke\u2019s Hospital (J.T., S.A.-M., R.P., C.V.), Department of Paediatrics, Guardamangia MSD09, Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter E.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Royal Manchester Children\u2019s Hospital (P.E.C.), Pendlebury, Manchester M27 1HA, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Shalet","sequence":"additional","affiliation":[{"name":"Department of Endocrinology (S.S.), Christie Hospital, Wilmslow Road, Manchester M20 4BX, United 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GHF-1.","volume":"342","author":"Theill","year":"1989","journal-title":"Nature"},{"key":"2020071617482039100_R4","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/0092-8674(90)90067-O","article-title":"The POU-specific domain of Pit-1 is essential for sequence-specific, high affinity DNA binding and DNA-dependent Pit-1-Pit-1 interactions.","volume":"61","author":"Ingraham","year":"1990","journal-title":"Cell"},{"key":"2020071617482039100_R5","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1101\/gad.9.16.1992","article-title":"Pit-1 binding to specific DNA sites as a monomer or dimer determines gene-specific use of a tyrosine-dependent synergy domain.","volume":"9","author":"Holloway","year":"1995","journal-title":"Genes Dev"},{"key":"2020071617482039100_R6","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1126\/science.2831625","article-title":"Activation of cell-specific expression of rat growth hormone and prolactin genes by a common transcription factor.","volume":"239","author":"Nelson","year":"1988","journal-title":"Science"},{"key":"2020071617482039100_R7","first-page":"670","article-title":"Transcriptional control of GH expression and anterior pituitary development.","volume":"14","author":"Theill","year":"1993","journal-title":"Endocr Rev"},{"key":"2020071617482039100_R8","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1101\/gad.4.5.695","article-title":"Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors.","volume":"4","author":"Simmons","year":"1990","journal-title":"Genes Dev"},{"key":"2020071617482039100_R9","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/347528a0","article-title":"Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1.","volume":"347","author":"Li","year":"1990","journal-title":"Nature"},{"key":"2020071617482039100_R10","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/0006-291X(92)92281-2","article-title":"Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency.","volume":"189","author":"Ohta","year":"1992","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071617482039100_R11","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/ng0492-56","article-title":"Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene.","volume":"1","author":"Tatsumi","year":"1992","journal-title":"Nat Genet"},{"key":"2020071617482039100_R12","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1126\/science.257.5073.1118","article-title":"Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia.","volume":"257","author":"Pfaffle","year":"1992","journal-title":"Science"},{"key":"2020071617482039100_R13","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1126\/science.257.5073.1115","article-title":"A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency.","volume":"257","author":"Radovick","year":"1992","journal-title":"Science"},{"key":"2020071617482039100_R14","first-page":"2790","article-title":"A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency.","volume":"81","author":"Pellegrini-Bouiller","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617482039100_R15","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1651-2227.1999.tb14401.x","article-title":"Combined pituitary hormone deficiency: role of Pit-1 and Prop-1.","volume":"88","author":"Pfaffle","year":"1999","journal-title":"Acta Paediatr Suppl"},{"key":"2020071617482039100_R16","first-page":"2","article-title":"POU domain factors in the neuroendocrine system: lessons from developmental biology provide insights into human disease.","volume":"22","author":"Andersen","year":"2001","journal-title":"Endocr Rev"},{"key":"2020071617482039100_R17","first-page":"679","article-title":"A hot spot in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates.","volume":"80","author":"Cohen","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617482039100_R18","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1093\/hmg\/3.9.1565","article-title":"Monoallelic expression of normal mRNA in the PIT1 mutation heterozygotes with normal phenotype and biallelic expression in the abnormal phenotype.","volume":"3","author":"Okamoto","year":"1994","journal-title":"Hum Mol Genet"},{"key":"2020071617482039100_R19","first-page":"3127","article-title":"The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency.","volume":"80","author":"Zegher","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617482039100_R20","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s004310050723","article-title":"Combined pituitary deficiencies of growth hormone, thyroid stimulating hormone and prolactin due to Pit-1 gene mutation: a case report.","volume":"156","author":"Holl","year":"1997","journal-title":"Eur J Pediatr"},{"key":"2020071617482039100_R21","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/s004310050722","article-title":"Pituitary dwarfism in the R271W Pit-1 gene mutation.","volume":"156","author":"Aarskog","year":"1997","journal-title":"Eur J Pediatr"},{"key":"2020071617482039100_R22","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1089\/thy.1998.8.299","article-title":"Description of a Brazilian patient bearing the R271W Pit-1 gene mutation.","volume":"8","author":"Rodrigues Martineli","year":"1998","journal-title":"Thyroid"},{"key":"2020071617482039100_R23","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/S0022-3476(98)70405-6","article-title":"Severe congenital hypopituitarism with low prolactin levels and age-dependent anterior pituitary hypoplasia: a clue to a PIT-1 mutation.","volume":"132","author":"Ward","year":"1998","journal-title":"J Pediatr"},{"key":"2020071617482039100_R24","first-page":"98","article-title":"Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene.","volume":"49","author":"Brown","year":"1998","journal-title":"Horm Res"},{"issue":"Suppl 4","key":"2020071617482039100_R25","first-page":"1","article-title":"GH and TSH deficiency","volume":"105","author":"Pfaffle","year":"1997","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"2020071617482039100_R26","first-page":"2079","article-title":"Pro239Ser: a novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency.","volume":"83","author":"Pernasetti","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617482039100_R27","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1046\/j.1365-2265.2003.01781.x","article-title":"Combined pituitary hormone deficiency in Australian children: clinical and genetic correlates.","volume":"58","author":"McLennan","year":"2003","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071617482039100_R28","unstructured":"Turton JPG, Mehta A, Raza J, Woods KS, Tiulpakov A, Cassar J, Chong K, Thomas PQ, Eunice M, Ammini AC, Bouloux PM, Starzyk J, Hindmarsh PC, Dattani MT Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD). Clin Endocrinol (Oxf), in press"},{"key":"2020071617482039100_R29","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1515\/JPEM.2002.15.3.325","article-title":"A novel mutation in PIT-1: phenotypic variability in familial combined pituitary hormone deficiencies.","volume":"15","author":"Gat-Yablonski","year":"2002","journal-title":"J Pediatr Endocrinol Metab"},{"key":"2020071617482039100_R30","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1530\/eje.0.1480619","article-title":"The R271W mutant form of Pit-1 does not act as a dominant inhibitor of Pit-1 action to activate the promoters of GH and prolactin genes.","volume":"148","author":"Kishimoto","year":"2003","journal-title":"Eur J Endocrinol"},{"key":"2020071617482039100_R31","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1210\/er.2001-0030","article-title":"Molecular basis of combined pituitary hormone deficiencies.","volume":"23","author":"Cohen","year":"2002","journal-title":"Endocr Rev"},{"key":"2020071617482039100_R32","doi-asserted-by":"crossref","first-page":"5076","DOI":"10.1210\/jc.2001-011936","article-title":"Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes.","volume":"87","author":"Osorio","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617482039100_R33","doi-asserted-by":"crossref","first-page":"5189","DOI":"10.1242\/dev.128.24.5189","article-title":"Molecular effects of novel mutations in Hesx1\/HESX1 associated with human pituitary disorders.","volume":"128","author":"Brickman","year":"2001","journal-title":"Development"},{"key":"2020071617482039100_R34","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1172\/JCI18589","article-title":"A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction.","volume":"112","author":"Carvalho","year":"2003","journal-title":"J Clin Invest"},{"key":"2020071617482039100_R35","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1086\/323764","article-title":"Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4.","volume":"69","author":"Machinis","year":"2001","journal-title":"Am J Hum Genet"},{"key":"2020071617482039100_R36","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/humu.1380020503","article-title":"How sensitive is PCR-SSCP?","volume":"2","author":"Hayashi","year":"1993","journal-title":"Hum Mutat"},{"key":"2020071617482039100_R37","first-page":"942","article-title":"Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301,G302 in the PROP1 gene.","volume":"84","author":"Mendonca","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617482039100_R38","doi-asserted-by":"crossref","first-page":"4353","DOI":"10.1210\/jcem.86.9.7828","article-title":"Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation.","volume":"86","author":"Riepe","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071617482039100_R39","doi-asserted-by":"crossref","first-page":"25520","DOI":"10.1074\/jbc.270.43.25520","article-title":"In vivo mutational analysis of the DNA binding domain of the tissue-specific transcription factor, Pit-1.","volume":"270","author":"Liang","year":"1995","journal-title":"J Biol Chem"},{"key":"2020071617482039100_R40","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1365-2265.2005.02215.x","article-title":"An update on the biochemical diagnosis of congenital ACTH insufficiency.","volume":"62","author":"Mehta","year":"2005","journal-title":"Clin Endocrinol (Oxf)"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/90\/8\/4762\/10818074\/jcem4762.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/90\/8\/4762\/10818074\/jcem4762.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T01:04:12Z","timestamp":1626311052000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/90\/8\/4762\/2838500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,8,1]]},"references-count":40,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2005,8,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2005-0570","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,8,1]]}}}