A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder
(2009) Journal of Thrombosis and Haemostasis — Vol. 7, n° 8, p. 1356-1363 (2009)
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- Abstract
- Background: The physiological relevance of the collagen glycoprotein VI (GPVI) receptor was known prior to its recognition as a platelet membrane receptor as several patients lacking GPVI as a consequence of autoantibody inhibition presented with a mild bleeding diathesis. Remarkably, patients with a proven GPVI gene mutation have not yet been identified. Results: In the present study, we describe a patient with a lifelong history of bleeding problems, structurally normal platelets but a functional platelet defect. Platelet aggregations are normal except for an absent response to Horm collagen, convulxin and the collagen-related peptide (CRP). ATP dense granule secretion is normal with ADP but absent with Horm collagen. Thrombus formation on a collagen surface in flowing blood is reduced but more single platelets are attached. Remarkably, the platelet function analyzer-100 shows a shortened collagen/ADP closure time. Flow cytometry demonstrates an absent expression of GPVI whereas immunoblot analysis shows strongly reduced levels of GPVI. The patient is compound heterozygous for an out-of-frame 16-bp deletion and a missense mutation S175N in a highly conserved residue of the 2nd Ig-like GPVI domain. The parents without clinical bleeding problems are heterozygous carriers. The mother carries the S175N mutation and presents with a mild functional platelet defect. In vitro studies show a reduced membrane expression and convulxin binding with the mutated S175N compared with the wild-type (WT) GPVI receptor. Conclusions: This study presents the first patient with a proven genetic GPVI defect.
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Hermans, C., Wittevrongel, C., Thys, C., Smethurst, P. A., Van Geet, C., & Freson, K. (2009). A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder. Journal of Thrombosis and Haemostasis, 7(8), 1356-1363. https://doi.org/10.1111/j.1538-7836.2009.03520.x (Original work published 2009)