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A Maternal Epimutation of GNAS Leads to Albright Osteodystrophy and Parathyroid Hormone Resistance

Institut National de la Santé et de la Recherche Médicale U561 (V.M., S.M.-M., C.S., A.L.) and Paediatric Endocrinology (A.L.), Paris V University, St-Vincent de Paul Hospital, 75014 Paris, France; and Department of Genetic and Human Reproduction (M.-L.K.), Centre Hospitalier Universitaire, 14033 Caen, France

Address all correspondence and requests for reprints to: Agnès Linglart, Pediatric Endocrinology and Institut National de la Santé et de la Recherche Médicale U561, Hôpital St-Vincent de Paul, 82 avenue Denfert-Rochereau, 75014 Paris, France. E-mail: agnes.linglart{at}svp.aphp.fr.

Context: Pseudohypoparathyroidism (PHP) type Ia is a rare maternally transmitted disease due to maternal loss-of-function mutations of GNAS, the gene encoding G_s, the -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 G_s expression in specific tissues.

Objective and Results: We report a girl with obvious Albright osteodystrophy features, PTH resistance, normal G_s 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 G_s 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.