Abstract
The GNAS locus on chromosome 20q13.11 is the archetypal complex imprinted locus. It comprises a bewildering array of alternative transcripts determined by differentially imprinted promoters which encode distinct proteins. It also provides the classic example of tissue‐specific imprinted gene expression, in which the canonical GNAS transcript coding for Gsα is expressed predominantly from the maternal allele in a set of seemingly unrelated tissues. Functionally, this rather obscure imprinting is nevertheless of considerable clinical significance, as it dictates the nature of the disease caused by inactivating mutations in Gsα, with end organ hormone resistance specifically on maternal transmission (pseudohypoparathyroidism type 1a, PHP1a). In addition, there is a bona fide imprinting disorder, PHP1b, which is caused specifically by DNA methylation defects in the differentially methylated regions (DMRs) that determine tissue‐specific monoallelic expression of GNAS. Although the genetic defect in PHP1a and the disrupted imprinting in PHP1b both essentially result in profound reduction of Gsα activity in tissues with monoallelic GNAS expression, and despite a growing awareness of the overlap in these two conditions, there are important pathophysiological differences between the two whose basis is not fully understood. PHP1b is one of the only imprinted gene syndromes in which cis‐acting mutations have been discovered that disrupt methylation of germline‐derived imprint marks; such imprinting mutations in GNAS are helping to provide important new insights into the mechanisms of imprinting establishment generally. © 2010 Wiley‐Liss, Inc.