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Endocrine Abstracts (2011) 26 S25.1

The Babraham Institute, Cambridge, UK.


Genomic imprinting is an epigenetic mechanism by which a subset of our genes displays unequal expression of the maternal and paternal alleles; in many cases, one allele is fully silenced. It occurs because these genes are marked differently (by DNA methylation and/or histone modifications) in male and female gametes. These gamete-specific marks are maintained at fertilisation and perpetuated throughout development and adult life, such that the alleles of imprinted genes retain a permanent memory of the parent in which they originated.

The GNAS locus on chromosome 20q13.11 (and chromosome 2 in mouse) is the archetypal complex imprinted locus. It comprises a set of overlapping transcripts determined by alternative promoters with different patterns of imprinted expression. It also provides the classic example of tissue-specific imprinting, in which the canonical GNAS transcript coding for Gsα is expressed predominantly from the maternal allele in some tissues. Functionally, this incomplete imprinting is clinically significant, 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 to Gsα, the locus encodes the proteins XLαs and NESP55 from the overlapping transcripts. XLαs is expressed exclusively from the paternal allele and functions similarly to Gsα at the biochemical level. However, gene knock-out studies in mice show that Gsα and XLαs have opposite physiological effects, for example, in sympathetic nervous activity and metabolism, suggesting that XLαs acts as a counter-regulator of pathways dependent on Gsα. Despite the importance of XLαs demonstrated in the mouse, the impact of XLαs function in human is not understood.

An alternative form of pseudohypoparathyroidism, PHP1b, is an imprinting disorder characterised by DNA methylation defects in the differentially methylated regions (DMRs) that determine tissue-specific monoallelic expression of GNAS. Aberrant DNA methylation in PHP1b is caused by deletions in cis, and these mutations are helping to provide insights into the mechanisms of imprinting establishment at GNAS and generally.

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