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GNAS1 Lesions in Pseudohypoparathyroidism Ia and Ic: Genotype Phenotype Relationship and Evidence of the Maternal Transmission of the Hormonal Resistance

Department of Pediatric Endocrinology (A.L., J.C.C.), Groupe Hospitalier Cochin-Saint Vincent de Paul, Assisvance Publique-Hôpitaux de Paris, 75014 Paris, France; Centre National de la Recherche Scientifique Unity 1524 (M.G.), Groupe Hospitalier Cochin-Saint Vincent de Paul, 75014 Paris, France; Department of Biochemistry (T.L., M.L.K.), Unity of Molecular Genetics, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, 75013 Paris, France; Department of Pediatrics (E.M.), 76000 Rouen, France; Departmènt of Genetics and Reproduction (M.L.K.), Centre Hospitalo-Universitaire, 14033 Caen, France

Address all correspondence and requests for reprints to: Prof. Marie-Laure Kottler, Département Génétique et Reproduction, Hôpital Clémenceau, 14033 Caen, France. E-mail: kottler-ml{at}chu-caen.fr

We conducted clinical and biological studies including screening for mutations in the gene encoding the subunit of G_s (GNAS1) in 30 subjects (21 unrelated families) with Albright’s hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte G_s activity (PHP-Ia; n = 19); AHO and decreased erythrocyte G_s activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte G_s activity (PHP-Ic; n = 1). A heterozygous GNAS1 gene lesion was found in 14 of 17 PHP-Ia index cases (82%), including 11 new mutations and a mutational hot-spot involving codons 189–190 (21%). These lesions lead to a truncated protein in all but three cases with missense mutations R280K, V159M, and D156N. In the patient diagnosed with PHP-Ic, G_s protein was shortened by just four amino acids, a finding consistent with the conservation of G_s activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in individuals with isolated AHO that were not relatives to PHP-Ia patients (n = 5). Intrafamilial segregation analyses of the mutated GNAS1 allele in nine PHP-Ia patients established that the mutation had either occurred de novo on the maternal allele (n = 4) or had been transmitted by a mother with a mild phenotype (n = 5). This finding is consistent with an imprinting of GNAS1 playing a role in the clinical phenotype of loss of function mutations and with a functional maternal GNAS1 allele having a predominant role in preventing the hormonal resistance of PHP-Ia.

Abbreviations: AC, Adenylyl cyclase; AHO, Albright’s hereditary osteodystrophy; PHP, pseudohypoparathyroidism.

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