Thromb Haemost 1998; 80(04): 546-550
DOI: 10.1055/s-0037-1615417
Rapid Communication
Schattauer GmbH

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

J. P. Scott III
1   From the Blood Research Institute, The Blood Center of Southeastern Wisconsin
,
J. P. Scott II
1   From the Blood Research Institute, The Blood Center of Southeastern Wisconsin
2   From the Children’s Hospital of Wisconsin
,
Y.-L. Chao
1   From the Blood Research Institute, The Blood Center of Southeastern Wisconsin
,
P. J. Newman
1   From the Blood Research Institute, The Blood Center of Southeastern Wisconsin
3   From the Departments of Cellular Biology and Pharmacology, Medical College of Wisconsin, Milwaukee, WI, USA
,
C. M. Ward
1   From the Blood Research Institute, The Blood Center of Southeastern Wisconsin
› Author Affiliations
Further Information

Publication History

Received 16 September 1997

Accepted after revision 01 July 1998

Publication Date:
08 December 2017 (online)

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Summary

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 hydro-pathy 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.