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GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance.
J Clin Endocrinol Metab. 2002 Jan; 87(1):189-97.JC

Abstract

We conducted clinical and biological studies including screening for mutations in the gene encoding the alpha 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)alpha 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.

Authors+Show Affiliations

Department of Pediatric Endocrinology, Groupe Hospitalier Cochin-Saint Vincent de Paul, Assisvance Publique-Hôpitaux de Paris, 75014 Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

11788646

Citation

Linglart, Agnès, et al. "GNAS1 Lesions in Pseudohypoparathyroidism Ia and Ic: Genotype Phenotype Relationship and Evidence of the Maternal Transmission of the Hormonal Resistance." The Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 1, 2002, pp. 189-97.
Linglart A, Carel JC, Garabédian M, et al. GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab. 2002;87(1):189-97.
Linglart, A., Carel, J. C., Garabédian, M., Lé, T., Mallet, E., & Kottler, M. L. (2002). GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. The Journal of Clinical Endocrinology and Metabolism, 87(1), 189-97.
Linglart A, et al. GNAS1 Lesions in Pseudohypoparathyroidism Ia and Ic: Genotype Phenotype Relationship and Evidence of the Maternal Transmission of the Hormonal Resistance. J Clin Endocrinol Metab. 2002;87(1):189-97. PubMed PMID: 11788646.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. AU - Linglart,Agnès, AU - Carel,Jean Claude, AU - Garabédian,Michèle, AU - Lé,Tran, AU - Mallet,Eric, AU - Kottler,Marie Laure, PY - 2002/1/15/pubmed PY - 2002/2/8/medline PY - 2002/1/15/entrez SP - 189 EP - 97 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 87 IS - 1 N2 - We conducted clinical and biological studies including screening for mutations in the gene encoding the alpha 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)alpha 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. SN - 0021-972X UR - https://www.unboundmedicine.com/medline/citation/11788646/GNAS1_lesions_in_pseudohypoparathyroidism_Ia_and_Ic:_genotype_phenotype_relationship_and_evidence_of_the_maternal_transmission_of_the_hormonal_resistance_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem.87.1.8133 DB - PRIME DP - Unbound Medicine ER -