iloprost and Hypoparathyroidism

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.

Topics: Abnormalities, Multiple; Adenosine; Adenylyl Cyclases; Adolescent; Alprostadil; Alternative Splicing; Amino Acid Sequence; Amino Acid Substitution; Bleeding Time; Blood Platelets; Child; Chromogranins; Cyclic AMP; Female; Fingers; Gene Frequency; Genomic Imprinting; GTP-Binding Protein alpha Subunits, Gs; Hemorrhagic Disorders; Heterotrimeric GTP-Binding Proteins; Humans; Hyperkinesis; Hypoparathyroidism; Iloprost; Intellectual Disability; Male; Molecular Sequence Data; Muscle Hypotonia; Mutagenesis, Insertional; Nerve Tissue Proteins; Phenotype; Platelet Aggregation; Platelet Function Tests; Polymorphism, Genetic; Protein Subunits; Repetitive Sequences, Amino Acid; Risk Factors; Second Messenger Systems; Structure-Activity Relationship; Wounds and Injuries