Thromb Haemost 2001; 86(03): 733-738
DOI: 10.1055/s-0037-1616126
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Genetic Variation of the Extra-large Stimulatory G Protein α-Subunit Leads to Gs Hyperfunction in Platelets and Is a Risk Factor for Bleeding

Kathleen Freson
1  Center for Molecular and Vascular Biology
,
Marc F. Hoylaerts
1  Center for Molecular and Vascular Biology
,
Jaak Jaeken
2  Department of Pediatrics, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
,
Marijke Eyssen
2  Department of Pediatrics, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
,
Jozef Arnout
1  Center for Molecular and Vascular Biology
,
Jos Vermylen
1  Center for Molecular and Vascular Biology
,
Chris Van Geet
1  Center for Molecular and Vascular Biology
2  Department of Pediatrics, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
› Author Affiliations
Further Information

Publication History

Received 16 February 2001

Accepted after revision 11 May 2001

Publication Date:
14 December 2017 (online)

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.