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.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
MeSH terms
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Abnormalities, Multiple / genetics*
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Adenosine / pharmacology
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Adenylyl Cyclases / metabolism
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Adolescent
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Alprostadil / pharmacology
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Alternative Splicing
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Amino Acid Sequence
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Amino Acid Substitution
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Bleeding Time
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Blood Platelets / physiology*
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Child
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Chromogranins
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Cyclic AMP / biosynthesis
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Female
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Fingers / abnormalities
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GTP-Binding Protein alpha Subunits, Gs / genetics*
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Gene Frequency
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Genomic Imprinting
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Hemorrhagic Disorders / epidemiology
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Hemorrhagic Disorders / genetics*
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Heterotrimeric GTP-Binding Proteins*
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Humans
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Hyperkinesis / genetics
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Hypoparathyroidism / genetics*
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Iloprost / pharmacology
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Intellectual Disability / genetics*
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Male
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Molecular Sequence Data
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Muscle Hypotonia / genetics
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Mutagenesis, Insertional
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Nerve Tissue Proteins*
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Phenotype
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Platelet Aggregation / drug effects
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Platelet Function Tests
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Polymorphism, Genetic
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Protein Subunits
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Repetitive Sequences, Amino Acid
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Risk Factors
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Second Messenger Systems
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Structure-Activity Relationship
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Wounds and Injuries / complications
Substances
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Chromogranins
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Nerve Tissue Proteins
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Protein Subunits
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Cyclic AMP
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GNAS protein, human
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GTP-Binding Protein alpha Subunits, Gs
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Heterotrimeric GTP-Binding Proteins
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Adenylyl Cyclases
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Alprostadil
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Iloprost
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Adenosine