GNAS1 imprinting: the latest twist

Abstract

In all branches of science, results that appear anomalous or depart from the norm force us to rethink the rules and challenge accepted dogma. The discovery that some genes are imprinted was one such departure. Whereas in classical mendelian genetics, the parental origin of a gene is unimportant, a small proportion of genes are imprinted with a ‘memory’ of whether they are maternally or paternally derived, and their transcription patterns are set accordingly. These imprints are often uncovered by unusual patterns of inheritance of genetic diseases.The GNAS1 locus on human chromosome 20 is already known to be complex. At least three transcripts derive from various combinations of exons: NESP55 is maternally expressed, XLαs is paternally expressed, and Gsα is biallelically expressed in most tissues, but imprinted in a few. Imprinting of this locus was first indicated by the unusual inheritance observed in families with Albright hereditary osteodystrophy (AHO), a condition characterized by short stature, developmental delay, obesity and metaphalangeal shortening. Some AHO patients also show pseudohypoparathyroidism type 1A (PHP1A), a resistance to the effects of several hormones, particularly parathyroid hormone and thyroid-stimulating hormone. PHP1A almost always results from maternally inherited mutations of Gsα; paternal transmission of the same mutation in the same family causes AHO without hormone resistance. This could be explained if Gsα is imprinted in the target sites for these hormones; for instance, the thyroid and renal tubule.A study by Shore and colleagues [1xPaternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. Shore, E.M et al. New Engl. J. Med. 2002; 346: 99–106CrossRef | PubMed | Scopus (144)See all References][1] now shows that even this view is simplistic. First, they demonstrate that mutations of Gsα can give rise to a very different condition, progressive osseous heteroplasia (POH), in which extensive inappropriate bone formation in soft tissue causes progressive disability. In some cases, the POH mutations were identical to those already described in families with AHO. Where the parental origin could be determined, the mutations were all paternally derived. Two transmitting fathers were not clinically affected themselves. Most intriguingly, in one family where three females with POH passed the mutation on, their children were affected by AHO, not POH. The hormone status of these children is not mentioned, so it is unclear whether they have PHP1A.So why do paternally inherited Gsα mutations lead to AHO in some families and POH in others? Existing models of imprinting cannot fully explain these observations, and further analysis of potential genetic and epigenetic modifiers is required. This complex locus and its associated genetic disorders have yet more interesting biological secrets to yield.