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Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy.
J Clin Endocrinol Metab. 1999 Sep; 84(9):3254-9.JC

Abstract

Albright hereditary osteodystrophy (AHO) is a genetic disorder characterized by short stature, skeletal defects, and obesity. Within AHO kindreds, some affected family members have only the somatic features of AHO [pseudopseudohypoparathyroidism (PPHP)], whereas others have these features in association with resistance to multiple hormones that stimulate adenylyl cyclase within their target tissues [pseudohypoparathyroidism type Ia (PHP Ia)]. Affected members of most AHO kindreds (both those with PPHP and those with PHP Ia) have a partial deficiency of Gs alpha, the alpha-subunit of the G protein that couples receptors to adenylyl cyclase stimulation, and in a number of cases heterozygous loss of function mutations within the Gs alpha gene (GNAS1) have been identified. Using PCR with the attachment of a high melting domain (GC-clamp) and temperature gradient gel electrophoresis, two novel heterozygous frameshift mutations within GNAS1 were found in two AHO kindreds. In one kindred all affected members (both PHP Ia and PPHP) had a heterozygous 2-bp deletion in exon 8, whereas in the second kindred a heterozygous 2-bp deletion in exon 4 was identified in all affected members examined. In both cases the frameshift encoded a premature termination codon several codons downstream of the deletion. In the latter kindred affected members were previously shown to have decreased levels of GNAS1 messenger ribonucleic acid expression. These results further underscore the genetic heterogeneity of AHO and provides further evidence that PHP Ia and PPHP are two clinical presentations of a common genetic defect. Serial measurements of thyroid function in members of kindred 1 indicate that TSH resistance progresses with age and becomes more evident after the first year of life.

Authors+Show Affiliations

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10487696

Citation

Yu, D, et al. "Identification of Two Novel Deletion Mutations Within the Gs Alpha Gene (GNAS1) in Albright Hereditary Osteodystrophy." The Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 9, 1999, pp. 3254-9.
Yu D, Yu S, Schuster V, et al. Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy. J Clin Endocrinol Metab. 1999;84(9):3254-9.
Yu, D., Yu, S., Schuster, V., Kruse, K., Clericuzio, C. L., & Weinstein, L. S. (1999). Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy. The Journal of Clinical Endocrinology and Metabolism, 84(9), 3254-9.
Yu D, et al. Identification of Two Novel Deletion Mutations Within the Gs Alpha Gene (GNAS1) in Albright Hereditary Osteodystrophy. J Clin Endocrinol Metab. 1999;84(9):3254-9. PubMed PMID: 10487696.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy. AU - Yu,D, AU - Yu,S, AU - Schuster,V, AU - Kruse,K, AU - Clericuzio,C L, AU - Weinstein,L S, PY - 1999/9/16/pubmed PY - 1999/9/16/medline PY - 1999/9/16/entrez SP - 3254 EP - 9 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 84 IS - 9 N2 - Albright hereditary osteodystrophy (AHO) is a genetic disorder characterized by short stature, skeletal defects, and obesity. Within AHO kindreds, some affected family members have only the somatic features of AHO [pseudopseudohypoparathyroidism (PPHP)], whereas others have these features in association with resistance to multiple hormones that stimulate adenylyl cyclase within their target tissues [pseudohypoparathyroidism type Ia (PHP Ia)]. Affected members of most AHO kindreds (both those with PPHP and those with PHP Ia) have a partial deficiency of Gs alpha, the alpha-subunit of the G protein that couples receptors to adenylyl cyclase stimulation, and in a number of cases heterozygous loss of function mutations within the Gs alpha gene (GNAS1) have been identified. Using PCR with the attachment of a high melting domain (GC-clamp) and temperature gradient gel electrophoresis, two novel heterozygous frameshift mutations within GNAS1 were found in two AHO kindreds. In one kindred all affected members (both PHP Ia and PPHP) had a heterozygous 2-bp deletion in exon 8, whereas in the second kindred a heterozygous 2-bp deletion in exon 4 was identified in all affected members examined. In both cases the frameshift encoded a premature termination codon several codons downstream of the deletion. In the latter kindred affected members were previously shown to have decreased levels of GNAS1 messenger ribonucleic acid expression. These results further underscore the genetic heterogeneity of AHO and provides further evidence that PHP Ia and PPHP are two clinical presentations of a common genetic defect. Serial measurements of thyroid function in members of kindred 1 indicate that TSH resistance progresses with age and becomes more evident after the first year of life. SN - 0021-972X UR - https://www.unboundmedicine.com/medline/citation/10487696/Identification_of_two_novel_deletion_mutations_within_the_Gs_alpha_gene__GNAS1__in_Albright_hereditary_osteodystrophy_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem.84.9.5970 DB - PRIME DP - Unbound Medicine ER -