Imprinting on chromosome 20: Tissue‐specific imprinting and imprinting mutations in the<i>GNAS</i>locus

AbstractTheGNASlocus 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 canonicalGNAStranscript 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 abona fideimprinting disorder, PHP1b, which is caused specifically by DNA methylation defects in the differentially methylated regions (DMRs) that determine tissue‐specific monoallelic expression ofGNAS. Although the genetic defect in PHP1a and the disrupted imprinting in PHP1b both essentially result in profound reduction of Gsα activity in tissues with monoallelicGNASexpression, and despite a growing awareness of the ov