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  • Title: A maternal epimutation of GNAS leads to Albright osteodystrophy and parathyroid hormone resistance.
    Author: Mariot V, Maupetit-Méhouas S, Sinding C, Kottler ML, Linglart A.
    Journal: J Clin Endocrinol Metab; 2008 Mar; 93(3):661-5. PubMed ID: 18182455.
    Abstract:
    CONTEXT: Pseudohypoparathyroidism (PHP) type Ia is a rare maternally transmitted disease due to maternal loss-of-function mutations of GNAS, the gene encoding Galphas, the alpha-stimulatory subunit of the G protein. Affected individuals display hormonal resistance (mainly PTH and TSH resistance) and Albright hereditary osteodystrophy. PHP type Ib (PHP-Ib), usually defined by isolated renal resistance to PTH and sometimes mild TSH resistance, is due to a maternal loss of GNAS exon A/B methylation, leading to decreased Galphas expression in specific tissues. OBJECTIVE AND RESULTS: We report a girl with obvious Albright osteodystrophy features, PTH resistance, normal Galphas bioactivity in red blood cells, yet no loss-of-function mutation in the GNAS coding sequence (exons 1-13). The methylation analysis of the four GNAS differentially methylated regions, i.e. NESP, AS, XL, and A/B, revealed broad methylation changes at all differentially methylated regions, including GNAS exon A/B, leading to a paternal epigenotype on both alleles. CONCLUSIONS: This observation suggests that: 1) the decreased expression of Galphas due to GNAS epimutations is not restricted to the renal tubule but may affect nonimprinted tissues like bone; 2) PHP-Ib is a heterogeneous disorder that should lead to studying GNAS epigenotype in patients with PHP and no mutation in GNAS exons 1-13, regardless of their physical features.
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