Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency.

2.50
Hdl Handle:
http://hdl.handle.net/10541/76594
Title:
Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency.
Authors:
Turton, James P; Reynaud, Rachel; Mehta, Ameeta; Torpiano, John; Saveanu, Alexandru; Woods, Kathryn S; Tiulpakov, Anatoly; Zdravkovic, Vera; Hamilton, Jill; Attard-Montalto, Simon; Parascandalo, Ray; Vella, Cecil; Clayton, Peter E; Shalet, Stephen M; Barton, John; Brue, Thierry; Dattani, Mehul T
Abstract:
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. OBJECTIVE: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1. 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. 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.
Affiliation:
Biochemistry, Endocrinology, and Metabolism Unit and London Centre for Paediatric Endocrinology, Institute of Child Health, London, United Kingdom.
Citation:
Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. 2005, 90 (8):4762-70 J. Clin. Endocrinol. Metab.
Journal:
The Journal of Clinical Endocrinology and Metabolism
Issue Date:
Aug-2005
URI:
http://hdl.handle.net/10541/76594
DOI:
10.1210/jc.2005-0570
PubMed ID:
15928241
Type:
Article
Language:
en
ISSN:
0021-972X
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorTurton, James P-
dc.contributor.authorReynaud, Rachel-
dc.contributor.authorMehta, Ameeta-
dc.contributor.authorTorpiano, John-
dc.contributor.authorSaveanu, Alexandru-
dc.contributor.authorWoods, Kathryn S-
dc.contributor.authorTiulpakov, Anatoly-
dc.contributor.authorZdravkovic, Vera-
dc.contributor.authorHamilton, Jill-
dc.contributor.authorAttard-Montalto, Simon-
dc.contributor.authorParascandalo, Ray-
dc.contributor.authorVella, Cecil-
dc.contributor.authorClayton, Peter E-
dc.contributor.authorShalet, Stephen M-
dc.contributor.authorBarton, John-
dc.contributor.authorBrue, Thierry-
dc.contributor.authorDattani, Mehul T-
dc.date.accessioned2009-08-06T15:14:55Z-
dc.date.available2009-08-06T15:14:55Z-
dc.date.issued2005-08-
dc.identifier.citationNovel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. 2005, 90 (8):4762-70 J. Clin. Endocrinol. Metab.en
dc.identifier.issn0021-972X-
dc.identifier.pmid15928241-
dc.identifier.doi10.1210/jc.2005-0570-
dc.identifier.urihttp://hdl.handle.net/10541/76594-
dc.description.abstractCONTEXT: 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. OBJECTIVE: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1. 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. 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.en
dc.language.isoenen
dc.subject.meshAmino Acid Sequence-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshFemale-
dc.subject.meshGenomics-
dc.subject.meshHuman Growth Hormone-
dc.subject.meshHumans-
dc.subject.meshHypopituitarism-
dc.subject.meshMagnetic Resonance Imaging-
dc.subject.meshMale-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshMutation, Missense-
dc.subject.meshPedigree-
dc.subject.meshPhenotype-
dc.subject.meshPituitary Gland, Anterior-
dc.subject.meshPituitary Gland, Posterior-
dc.subject.meshPolymorphism, Genetic-
dc.subject.meshRetrospective Studies-
dc.subject.meshTranscription Factor Pit-1-
dc.subject.meshTranscription Factors-
dc.titleNovel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency.en
dc.typeArticleen
dc.contributor.departmentBiochemistry, Endocrinology, and Metabolism Unit and London Centre for Paediatric Endocrinology, Institute of Child Health, London, United Kingdom.en
dc.identifier.journalThe Journal of Clinical Endocrinology and Metabolismen

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