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Gs(alpha) mutations and imprinting defects in human disease.
Ann N Y Acad Sci. 2002 Jun; 968:173-97.AN

Abstract

Gs is the ubiquitously expressed heterotrimeric G protein that couples receptors to the effector enzyme adenylyl cyclase and is required for receptor-stimulated intracellular cAMP generation. Activated receptors promote the exchange of GTP for GDP on the Gs alpha-subunit (Gs(alpha)), resulting in Gs activation; an intrinsic GTPase activity of Gs(alpha) deactivates Gs by hydrolyzing bound GTP to GDP. Mutations of Gs(alpha) residues involved in the GTPase reaction that lead to constitutive activation are present in endocrine tumors, fibrous dysplasia of bone, and McCune-Albright syndrome. Heterozygous loss-of-function mutations lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, and skeletal defects, and are sometimes associated with progressive osseous heteroplasia. Maternal transmission of Gs(alpha) mutations leads to AHO plus resistance to several hormones (e.g., parathyroid hormone) that activate Gs in their target tissues (pseudohypoparathyroidism type IA), while paternal transmission leads only to the AHO phenotype (pseudopseudohypoparathyroidism). Studies in both mice and humans demonstrate that Gs(alpha) is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues and biallelically expressed in most other tissues. This likely explains why multihormone resistance occurs only when Gs(alpha) mutations are inherited maternally. The Gs(alpha) gene GNAS1 has at least four alternative promoters and first exons, leading to the production of alternative gene products including Gs(alpha), XL alphas (a novel Gs(alpha) isoform expressed only from the paternal allele), and NESP55 (a chromogranin-like protein expressed only from the maternal allele). The fourth alternative promoter and first exon (exon 1A) located just upstream of the Gs(alpha) promoter is normally methylated on the maternal allele and is transcriptionally active on the paternal allele. In patients with parathyroid hormone resistance but without AHO (pseudohypoparathyroidism type IB), the exon 1A promoter region is unmethylated and transcriptionally active on both alleles. This GNAS1 imprinting defect is predicted to decrease Gs(alpha) expression in tissues where Gs(alpha) is normally imprinted and therefore to lead to renal parathyroid hormone resistance.

Authors+Show Affiliations

Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. leew@amb.niddk.nih.govNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

12119276

Citation

Weinstein, Lee S., et al. "Gs(alpha) Mutations and Imprinting Defects in Human Disease." Annals of the New York Academy of Sciences, vol. 968, 2002, pp. 173-97.
Weinstein LS, Chen M, Liu J. Gs(alpha) mutations and imprinting defects in human disease. Ann N Y Acad Sci. 2002;968:173-97.
Weinstein, L. S., Chen, M., & Liu, J. (2002). Gs(alpha) mutations and imprinting defects in human disease. Annals of the New York Academy of Sciences, 968, 173-97.
Weinstein LS, Chen M, Liu J. Gs(alpha) Mutations and Imprinting Defects in Human Disease. Ann N Y Acad Sci. 2002;968:173-97. PubMed PMID: 12119276.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gs(alpha) mutations and imprinting defects in human disease. AU - Weinstein,Lee S, AU - Chen,Min, AU - Liu,Jie, PY - 2002/7/18/pubmed PY - 2002/8/21/medline PY - 2002/7/18/entrez SP - 173 EP - 97 JF - Annals of the New York Academy of Sciences JO - Ann. N. Y. Acad. Sci. VL - 968 N2 - Gs is the ubiquitously expressed heterotrimeric G protein that couples receptors to the effector enzyme adenylyl cyclase and is required for receptor-stimulated intracellular cAMP generation. Activated receptors promote the exchange of GTP for GDP on the Gs alpha-subunit (Gs(alpha)), resulting in Gs activation; an intrinsic GTPase activity of Gs(alpha) deactivates Gs by hydrolyzing bound GTP to GDP. Mutations of Gs(alpha) residues involved in the GTPase reaction that lead to constitutive activation are present in endocrine tumors, fibrous dysplasia of bone, and McCune-Albright syndrome. Heterozygous loss-of-function mutations lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, and skeletal defects, and are sometimes associated with progressive osseous heteroplasia. Maternal transmission of Gs(alpha) mutations leads to AHO plus resistance to several hormones (e.g., parathyroid hormone) that activate Gs in their target tissues (pseudohypoparathyroidism type IA), while paternal transmission leads only to the AHO phenotype (pseudopseudohypoparathyroidism). Studies in both mice and humans demonstrate that Gs(alpha) is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues and biallelically expressed in most other tissues. This likely explains why multihormone resistance occurs only when Gs(alpha) mutations are inherited maternally. The Gs(alpha) gene GNAS1 has at least four alternative promoters and first exons, leading to the production of alternative gene products including Gs(alpha), XL alphas (a novel Gs(alpha) isoform expressed only from the paternal allele), and NESP55 (a chromogranin-like protein expressed only from the maternal allele). The fourth alternative promoter and first exon (exon 1A) located just upstream of the Gs(alpha) promoter is normally methylated on the maternal allele and is transcriptionally active on the paternal allele. In patients with parathyroid hormone resistance but without AHO (pseudohypoparathyroidism type IB), the exon 1A promoter region is unmethylated and transcriptionally active on both alleles. This GNAS1 imprinting defect is predicted to decrease Gs(alpha) expression in tissues where Gs(alpha) is normally imprinted and therefore to lead to renal parathyroid hormone resistance. SN - 0077-8923 UR - https://www.unboundmedicine.com/medline/citation/12119276/Gs_alpha__mutations_and_imprinting_defects_in_human_disease_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2002&volume=968&spage=173 DB - PRIME DP - Unbound Medicine ER -