Summary
Alternatively spliced GNAS1 and XL-GNAS1, encoding respectively the stimulatory G-protein
α-subunit (Gsα) and the extra-large stimulatory G-protein α-subunit (XLsα), are located
on the imprinted chromosomal region 20q13.12-13. We presently report a functional
polymorphism in the imprinted XL-GNAS1 gene. In three patients, a 36 bp insertion
and two basepair substitutions flanking this insertion were found in the paternally
inherited XL-GNAS1 exon 1. They clinically manifest an enhanced trauma-related bleeding
tendency and a variable degree of mental retardation. A platelet aggregation inhibition
test to evaluate Gs function was developed. Their platelets display Gs hyperfunction
and an enhanced cAMP generation upon stimulation of Gs-coupled receptors. The prevalence
of the XLsα insertion in a normal control group was 2.2%. Normal controls, inheriting
the insertion maternally, had a normal platelet Gs activity, whereas controls inheriting
the insertion paternally had increased inducible platelet Gs activity, defining the
insertion as a functional polymorphism. This paternally inherited XLsα insertion represents
a new genetic cause of an inherited bleeding tendency, although to a variable degree.
Keywords
Gs hyperfunction - XLsα - adenylyl cyclase - functional polymorphism - bleeding diathesis