Imprinting at the GNAS locus and endocrine disease
Part 1. Genetics
Published Online: 15 JUL 2005
Copyright © 2005 John Wiley & Sons, Ltd
Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics
How to Cite
Weinstein, L. S., Chen, M., Sakamoto, A. and Liu, J. 2005. Imprinting at the GNAS locus and endocrine disease. Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics. 1:1.3:31.
- Published Online: 15 JUL 2005
The ubiquitously expressed G protein α-subunit Gsα couples receptors to adenylyl cyclase and is required for the intracellular cyclic AMP response to hormones and other extracellular signals. Gsα is one of several gene products of the GNAS locus at 20q13. Gsα is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in hormone-target tissues such as renal proximal tubules, thyroid, ovary, and pituitary but biallelically expressed in most other tissues. Heterozygous Gsα null mutations result in Albright hereditary osteodystrophy (AHO), which is characterized by obesity, short stature, and skeletal defects, and is likely the result of Gsα haploinsufficiency in many tissues. Because of tissue-specific Gsα imprinting, patients who inherit their mutations maternally also develop resistance to multiple hormones (parathyroid hormone, thyrotropin) whose receptors activate Gsα (a condition referred to as pseudohypoparathyroidism type 1A), while patients who inherit their mutations paternally only develop AHO. Pseudohypoparathyroidism type 1B (PHPIB), in which patients develop parathyroid hormone (and sometimes thyrotropin) resistance in the absence of AHO, is caused by GNAS imprinting defects in which a paternal epigenotype is present on both parental alleles. This presumably leads to Gsα deficiency only in tissues where Gsα is normally imprinted. Familial PHPIB is usually associated with a deletion of a region within the closely linked STX16 gene that appears to be required for normal GNAS imprinting. Most likely, tissue-specific Gsα imprinting results from an indirect mechanism involving a closely linked differentially methylated region (DMR) whose imprinting is lost in PHPIB.
- genomic imprinting;
- G protein;
- parathyroid hormone;
- cyclic AMP;
- Albright hereditary osteodystrophy;
- McCune-Albright syndrome;
- fibrous dysplasia;