A frameshift mutation at Gly975 in the transmembrane domain of GPIIb prevents GPIIb-IIIa expression--analysis of two novel mutations in a kindred with type I glanzmann thrombasthenia. Thromb Haemost 1998 Oct;80(4):546-50
Date
11/03/1998Pubmed ID
9798966Scopus ID
2-s2.0-0031727360 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
Two Hispanic siblings presenting with lifelong mucocutaneous bleeding were diagnosed clinically with Glanzmann thrombasthenia on the basis of a normal platelet count, prolonged bleeding time and absent platelet aggregation in response to multiple agonists. Quantitative analysis of the probands' platelets by flow cytometry showed a complete absence of GPIIb-IIIa, consistent with Type I thrombasthenia. Genetic analysis showed the probands to be compound heterozygotes for two novel mutations of GPIIb: a C1414>G mutation in exon 14, resulting in a premature termination codon replacing residue Tyr440, and the insertion of a G at position 3016 in exon 29, leading to a frameshift affecting the C-terminal half of the transmembrane domain and the cytoplasmic tail. The frameshifted sequence alters residues from Gly975 onwards and is predicted to significantly alter the hydropathy and charge profiles of the GPIIb transmembrane domain. The Type I phenotype associated with this mutation suggests that GPIIb residues 975-1008 contain critical structural motifs for heterodimer assembly, membrane retention, export from the ER and surface expression.
Author List
Scott JP 3rd, Scott JP 2nd, Chao YL, Newman PJ, Ward CMAuthors
John Paul Scott MD Emeritus Professor in the Pediatrics department at Medical College of WisconsinJohn P. Scott MD Professor in the Anesthesiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Amino Acid SequenceFrameshift Mutation
Heterozygote
Humans
Molecular Sequence Data
Platelet Aggregation
Platelet Glycoprotein GPIIb-IIIa Complex
Thrombasthenia
