Genetic variation of the extra-large stimulatory G protein alpha-subunit leads to Gs hyperfunction in platelets and is a risk factor for bleeding

Alternatively spliced GNAS1 and XL-GNAS1, encoding respectively the stimula tory G-protein a-subunit (Gsa) and the extra-large stimulatory G-protein a- subunit (XLs alpha), are located on the imprinted chromosomal region 20q13. 12-13. We presently report a functional polymorphism in the imprinted XL-GN AS1 gene. In three patients, a 36 bp insertion and two basepair substitutio ns flanking this insertion were found in the paternally inherited XL-GNAS1 exon 1. They clinically manifest an enhanced trauma-related bleeding tenden cy and a variable degree of mental retardation. A platelet aggregation inhi bition test to evaluate Gs function was developed. Their platelets display Gs hyperfunction and an enhanced cAMP generation upon stimulation of Gs-cou pled receptors. The prevalence of the XLsa insertion in a normal control gr oup was 2.2%. Normal controls, inheriting the insertion maternally, had a n ormal platelet Gs activity, whereas controls inheriting the insertion pater nally had increased inducible platelet Gs activity, defining the insertion as a functional polymorphism. This paternally inherited YLs alpha insertion represents a new genetic cause of an inherited bleeding tendency, although to a variable degree.