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It also provides the classic example of tissue\u2010specific imprinted gene expression, in which the canonical<jats:italic>GNAS<\/jats:italic>transcript coding for Gs\u03b1 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 Gs\u03b1, with end organ hormone resistance specifically on maternal transmission (pseudohypoparathyroidism type 1a, PHP1a). In addition, there is a<jats:italic>bona fide<\/jats:italic>imprinting disorder, PHP1b, which is caused specifically by DNA methylation defects in the differentially methylated regions (DMRs) that determine tissue\u2010specific monoallelic expression of<jats:italic>GNAS<\/jats:italic>. Although the genetic defect in PHP1a and the disrupted imprinting in PHP1b both essentially result in profound reduction of Gs\u03b1 activity in tissues with monoallelic<jats:italic>GNAS<\/jats:italic>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<jats:italic>cis<\/jats:italic>\u2010acting mutations have been discovered that disrupt methylation of germline\u2010derived imprint marks; such imprinting mutations in<jats:italic>GNAS<\/jats:italic>are helping to provide important new insights into the mechanisms of imprinting establishment generally. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.c.30271","type":"journal-article","created":{"date-parts":[[2010,9,4]],"date-time":"2010-09-04T04:26:13Z","timestamp":1283574373000},"page":"377-386","source":"Crossref","is-referenced-by-count":71,"title":["Imprinting on chromosome 20: Tissue\u2010specific imprinting and imprinting mutations in 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