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    A novel MEN1 intronic mutation associated with multiple endocrine neoplasia type 1

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    Authors
    Lemos, Manuel C
    Harding, Brian
    Shalet, Stephen M
    Thakker, Rajesh V
    Affiliation
    Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
    Issue Date
    2007-05
    
    Metadata
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    Abstract
    OBJECTIVE: To investigate a family with an unusual combination of multiple endocrine neoplasia (MEN1) and the McCune-Albright syndrome for MEN1 mutations and activating GNAS1 mutations at codons Arg201 and Gln227. METHODS: DNA sequences analyses were performed of the MEN1 gene and codons Arg201 and Gln227 of the GNAS1 gene, using leucocyte and endocrine tissue DNA. RESULTS: A c-->g transversion at position -9 bp in intron 9 of the MEN1 gene was identified. This resulted in the generation of a BmrI restriction endonuclease site, and its presence and segregation with MEN1 in the family was demonstrated by restriction endonuclease analysis. The c-->g transversion was shown to result in the generation of a novel acceptor splice site (ccag) using reverse transcriptase-polymerase chain reaction (RT-PCR) and ribonucleic acid (RNA) obtained from Epstein-Barr virus (EBV)-transformed lymphoblasts. Utilization of this splice site resulted in an abnormal messenger RNA (mRNA) transcript that contained an additional eight bases. This predicted a frameshift that would result in nine missense amino acids followed by a premature termination signal. GNAS1 mutations were not detected in the patient with McCune-Albright syndrome. CONCLUSIONS: The occurrence of MEN1 and the McCune-Albright syndrome in this family are coincidental findings and not due to a common genetic aetiology. However, our results have identified a novel MEN1 mutation that occurs in intron 9 and generates a novel acceptor splice site. Such splicing-affecting genomic variants (SpaGVs) are increasingly being recognized as a cause of human disease, and are likely to be of significance in the 10% of MEN1 patients who do not have coding region mutations.
    Citation
    A novel MEN1 intronic mutation associated with multiple endocrine neoplasia type 1. 2007, 66 (5):709-13 Clin. Endocrinol.
    Journal
    Clinical Endocrinology
    URI
    http://hdl.handle.net/10541/70253
    DOI
    10.1111/j.1365-2265.2007.02806.x
    PubMed ID
    17388795
    Type
    Article
    Language
    en
    ISSN
    0300-0664
    ae974a485f413a2113503eed53cd6c53
    10.1111/j.1365-2265.2007.02806.x
    Scopus Count
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