title: Genetic variation of the extra-large stimulatory G protein alpha-subunit leads to Gs hyperfunction in platelets and is a risk factor for bleeding.
abstract: Alternatively spliced GNAS1 and XL-GNAS1, encoding respectively the stimulatory G-protein alpha-subunit (Gsalpha) and the extra-large stimulatory G-protein alpha-subunit (XLsalpha), 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 XLsalpha 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 XLsalpha insertion represents a new genetic cause of an inherited bleeding tendency, although to a variable degree.
authors.affiliation: Center for Molecular and Vascular Biology, University  Hospital Gasthuisberg, University of Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Freson
authors.forename: M F
authors.initials: MF
authors.lastname: Hoylaerts
authors.forename: J
authors.initials: J
authors.lastname: Jaeken
authors.forename: M
authors.initials: M
authors.lastname: Eyssen
authors.forename: J
authors.initials: J
authors.lastname: Arnout
authors.forename: J
authors.initials: J
authors.lastname: Vermylen
authors.forename: C
authors.initials: C
authors.lastname: Van Geet
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000241:Adenosine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000527:Alprostadil / Q000494:pharmacology; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D002648:Child; D002864:Chromogranins; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D005385:Fingers / Q000002:abnormalities; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005787:Gene Frequency; D018392:Genomic Imprinting; D006474:Hemorrhagic Disorders / Q000453:epidemiology / Q000235:genetics*; D020962:Heterotrimeric GTP-Binding Proteins; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics; D007011:Hypoparathyroidism / Q000235:genetics*; D016285:Iloprost / Q000494:pharmacology; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000235:genetics; D016254:Mutagenesis, Insertional; D009419:Nerve Tissue Proteins; D010641:Phenotype; D010974:Platelet Aggregation / Q000187:drug effects; D010979:Platelet Function Tests; D011110:Polymorphism, Genetic; D021122:Protein Subunits; D020449:Repetitive Sequences, Amino Acid; D012307:Risk Factors; D015290:Second Messenger Systems; D013329:Structure-Activity Relationship; D014947:Wounds and Injuries / Q000150:complications
chemical_list: D002864:Chromogranins; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D000242:Cyclic AMP; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000527:Alprostadil; D016285:Iloprost; D000241:Adenosine