Baroque imprints

Abstract

Imprinting – the expression or repression of an allele depending on its parent of origin – explains why in some genetic syndromes the same mutation can cause disease if it comes from one parent but have no effect if it comes from the other. Pseudohypoparathyroidism-IA (PHP-IA) appears to be an imprinting-affected disease: full-blown PHP-IA is maternally inherited whereas only a subset of symptoms are seen with paternal transmission. This paper 1 Hayward B.E. et al. Bidirectional imprinting of a single gene: GNAS1 encodes maternally and paternally, biallelically derived proteins. Proc. Natl. Acad. Sci. U. S. A. 1998; 9: 15475-15480 Crossref Scopus (265) Google Scholar addresses the problem that while the gene found to be mutant in PHP-IA, GNAS1, encodes two G-protein subunits, Gs and XLαs, neither seems to be expressed only from the maternal chromosome such as might account for PHP-IA proper: Gs is biallelically expressed and XLαs is paternally expressed. An interesting story emerged with the discovery of a third GNAS1 transcript, this time maternally expressed, encoding a neuroendocrine secretory protein NESP55. All three GNAS1 transcripts share exons 2–11 but have different first exons. The NESP55 coding region is, moreover, contained entirely in exon 1; exons 2–11, which are coding in Gs and XLαs, are untranslated. So one gene gives three products, one biallelically expressed, one paternally expressed and one maternally expressed. The authors also hint at the existence of antagonistic antisense transcripts, such as a maternally expressed XLαs-antisense transcript that cound interfere with XLαs expression from the paternal chromosome. Curiously, XLαs and NESP55, while they have no protein sequence homology, are both involved in the regulated secretory pathway in neuroendocrine tissues. It is most likely, therefore, that this locus did not evolve to its current state just by chance.