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Gs(alpha) mutations and imprinting defects in human disease
Lee S Weinstein1, Min Chen, Jie Liu
1Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. leew@amb.niddk.nih.gov
Annals of the New York Academy of Sciences
|July 18, 2002
Summary
The Gs alpha-subunit (Gsα) gene, GNAS1, exhibits tissue-specific imprinting, influencing hormone signaling. Imprinting defects in GNAS1 can cause parathyroid hormone resistance and Albright hereditary osteodystrophy (AHO).
Area of Science:
- Molecular Endocrinology
- Genetics
- G Protein Signaling
Background:
- Gs is a crucial heterotrimeric G protein mediating receptor-stimulated cAMP generation via adenylyl cyclase.
- Mutations in Gs alpha-subunit (Gsα) cause constitutive activation (endocrine tumors, McCune-Albright syndrome) or loss-of-function (Albright hereditary osteodystrophy - AHO).
- Parent-of-origin effects (imprinting) of Gsα mutations dictate disease phenotype, with maternal transmission causing hormone resistance (pseudohypoparathyroidism type IA) and paternal transmission leading to AHO.
Purpose of the Study:
- To investigate the role of GNAS1 imprinting in G protein signaling and associated disorders.
- To elucidate the molecular basis of tissue-specific Gsα expression and its impact on hormone resistance.
- To understand the mechanisms underlying pseudohypoparathyroidism type IB related to GNAS1 imprinting defects.
Main Methods:
- Analysis of GNAS1 gene structure, including alternative promoters and first exons.
- Investigation of Gsα imprinting patterns in human tissues.
- Examination of methylation status of the exon 1A promoter region in patients with pseudohypoparathyroidism type IB.
Main Results:
- Gsα is imprinted in a tissue-specific manner, primarily maternally expressed in some tissues and biallelically expressed in others.
- The GNAS1 gene produces multiple isoforms (Gsα, XLαs, NESP55) from alternative promoters.
- In pseudohypoparathyroidism type IB, the exon 1A promoter is unmethylated and biallelically active, leading to reduced Gsα expression and parathyroid hormone resistance.
Conclusions:
- Tissue-specific imprinting of GNAS1 is critical for normal G protein signaling and hormone responsiveness.
- Defects in GNAS1 imprinting, particularly affecting the exon 1A promoter, underlie pseudohypoparathyroidism type IB.
- Understanding GNAS1 imprinting provides insights into the pathogenesis of AHO and related disorders.