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; Marc F. Hoylaerts; Jaak Jaeken; Marijke Eyssen; Jozef Arnout; Jos Vermylen; Chris Van Geet

doi:10.1055/s-0037-1616126

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 86(03): 733-738
DOI: 10.1055/s-0037-1616126

In Focus

Schattauer GmbH

Genetic Variation of the Extra-large Stimulatory G Protein α-Subunit Leads to Gs Hyperfunction in Platelets and Is a Risk Factor for Bleeding

Autoren

Kathleen Freson

¹Center for Molecular and Vascular Biology
Marc F. Hoylaerts

¹Center for Molecular and Vascular Biology
Jaak Jaeken

²Department of Pediatrics, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
Marijke Eyssen

²Department of Pediatrics, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
Jozef Arnout

¹Center for Molecular and Vascular Biology
Jos Vermylen

¹Center for Molecular and Vascular Biology
Chris Van Geet

¹Center for Molecular and Vascular Biology

²Department of Pediatrics, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium

Abstract

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

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Referenzen

References
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