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

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    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
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    Affiliation
    Biochemistry, Endocrinology, and Metabolism Unit and London Centre for Paediatric Endocrinology, Institute of Child Health, London, United Kingdom.
    Issue Date
    2005-08
    
    Metadata
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    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.
    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
    URI
    http://hdl.handle.net/10541/76594
    DOI
    10.1210/jc.2005-0570
    PubMed ID
    15928241
    Type
    Article
    Language
    en
    ISSN
    0021-972X
    ae974a485f413a2113503eed53cd6c53
    10.1210/jc.2005-0570
    Scopus Count
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