A GNAS1 imprinting defect in pseudohypoparathyroidism type IB
Jie Liu, … , Leslie G. Biesecker, Lee S. Weinstein
Jie Liu, … , Leslie G. Biesecker, Lee S. Weinstein
Published November 1, 2000
Citation Information: J Clin Invest. 2000;106(9):1167-1174. https://doi.org/10.1172/JCI10431.
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Article

A GNAS1 imprinting defect in pseudohypoparathyroidism type IB

Abstract

Pseudohypoparathyroidism type IB (PHPIB) is characterized by renal resistance to parathyroid hormone (PTH) and the absence of other endocrine or physical abnormalities. Familial PHPIB has been mapped to 20q13, near GNAS1, which encodes Gsα, the G protein α-subunit required for receptor-stimulated cAMP generation. However, Gsα function is normal in blood cells from PHPIB patients, ruling out mutations within the Gsα coding region. In mice Gsα is expressed only from the maternal allele in renal proximal tubules (the site of PTH action) but is biallelically expressed in most other tissues. Studies in patients with Albright hereditary osteodystrophy suggest a similar Gsα imprinting pattern in humans. Here we identify a region upstream of the Gsα promoter that is normally methylated on the maternal allele and unmethylated on the paternal allele, but that is unmethylated on both alleles in all 13 PHPIB patients studied. Within this region is an alternative promoter and first exon (exon 1A), generating transcripts that are normally expressed only from the paternal allele, but that are biallelically expressed in PHPIB patients. Therefore, PHPIB is associated with a paternal-specific imprinting pattern of the exon 1A region on both alleles, which may lead to decreased Gsα expression in renal proximal tubules. We propose that loss of exon 1A imprinting is the cause of PHPIB.

Authors

Jie Liu, Deborah Litman, Marjorie J. Rosenberg, Shuhua Yu, Leslie G. Biesecker, Lee S. Weinstein

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Potential mechanisms for tissue-specific imprinting of Gsα. (a) The exon...
Potential mechanisms for tissue-specific imprinting of Gsα. (a) The exon 1A DMR may contain a binding site for a tissue-specific repressor (Rep) that binds to the paternal allele (Pat) in renal proximal tubules, leading to silencing of the Gsα (exon 1) promoter. Binding to the maternal allele (Mat) is prevented by methylation of the binding site. The model predicts that the repressor is expressed in renal proximal tubules, but not in other tissues where Gsα is biallelically expressed. (b) The exon 1A DMR may contain one or more boundary elements (B) that block activation of the Gsα promoter by an upstream enhancer (E) in the paternal allele, but do not block enhancer-promoter interactions in the maternal allele due to methylation. This is the mechanism by which Igf2 is imprinted (36, 37). This model predicts that expression of Gsα in other tissues is not dependent on the upstream enhancer.