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

• Published in: The journal of clinical endocrinology and metabolism Vol. 87; no. 1; pp. 189 - 197
• Main Authors: Linglart, Agnès, Carel, Jean Claude, Garabédian, Michèle, Lé, Tran, Mallet, Eric, Kottler, Marie Laure
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.01.2002; Endocrine Society
• Subjects: Adolescent; Adult; Alleles; Biological and medical sciences; Child; Child, Preschool; Codons; Endocrinopathies; Erythrocytes; Female; Fibrous Dysplasia, Polyostotic - genetics; Fundamental and applied biological sciences. Psychology; Genotype; Genotype & phenotype; Genotypes; GTP-Binding Protein alpha Subunits, Gs - deficiency; GTP-Binding Protein alpha Subunits, Gs - genetics; Hormone metabolism and regulation; Humans; Hypocalcemia - genetics; Imprinting; Infant; Infant, Newborn; Lesions; Male; Medical sciences; Middle Aged; Missense mutation; Mutation; Mutation hot spots; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Osteodystrophy; Parathyroids. Parafollicular cells. Cholecalciferol. Phosphocalcic homeostasis (diseases); Pedigree; Phenotype; Phenotypes; Pregnancy. Parturition. Lactation; Pseudohypoparathyroidism; Pseudohypoparathyroidism - blood; Pseudohypoparathyroidism - genetics; Vertebrates: reproduction; Endocrinopathy; Human; Typing; Family study; Genotype; Medical screening; Hereditary; Subunit; Genetic disease; Resistance; Symptomatology; Phenotype; Missense mutation; Gene; Pseudohypoparathyroidism
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jcem.87.1.8133

We conducted clinical and biological studies including screening for mutations in the gene encoding the α subunit of Gs (GNAS1) in 30 subjects (21 unrelated families) with Albright’s hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte Gs activity (PHP-Ia; n = 19); AHO and decreased erythrocyte Gs activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte Gs 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, Gsα protein was shortened by just four amino acids, a finding consistent with the conservation of Gs 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.