Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency.
Authors
Turton, James PReynaud, 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
Affiliation
Biochemistry, Endocrinology, and Metabolism Unit and London Centre for Paediatric Endocrinology, Institute of Child Health, London, United Kingdom.Issue Date
2005-08
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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.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 MetabolismDOI
10.1210/jc.2005-0570PubMed ID
15928241Type
ArticleLanguage
enISSN
0021-972Xae974a485f413a2113503eed53cd6c53
10.1210/jc.2005-0570
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