A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3.
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| Abstract |
Direct sequencing of VWF genomic DNA in 21 patients with type 3 von Willebrand disease (VWD) failed to reveal a causative homozygous or compound heterozygous VWF genotype in 5 cases. Subsequent analysis of VWF mRNA led to the discovery of a deletion (c.221-977_532 + 7059del [p.Asp75_Gly178del]) of VWF in 7 of 12 white type 3 VWD patients from 6 unrelated families. This deletion of VWF exons 4 and 5 was absent in 9 patients of Asian origin. We developed a genomic DNA-based assay for the deletion, which also revealed its presence in 2 of 34 type 1 VWD families, segregating with VWD in an autosomal dominant fashion. The deletion was associated with a specific VWF haplotype, indicating a possible founder origin. Expression studies indicated markedly decreased secretion and defective multimerization of the mutant VWF protein. Further studies have found the mutation in additional type 1 VWD patients and in a family expressing both type 3 and type 1 VWD. The c.221-977_532 + 7059del mutation represents a previously unreported cause of both types 1 and 3 VWD. Screening for this mutation in other type 1 and type 3 VWD patient populations is required to elucidate further its overall contribution to VWD arising from quantitative deficiencies of VWF.
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| Authors | Megan S Sutherland, Anthony M Cumming, Mackenzie Bowman, Paula H B Bolton-Maggs, Derrick J Bowen, Peter W Collins, Charles R M Hay, Andrew M Will, Stephen Keeney |
| Journal | Blood (Blood) Vol. 114 Issue 5 Pg. 1091-8 (Jul 30 2009) ISSN: 1528-0020 [Electronic] United States |
| PMID | 19372260 (Publication Type: Journal Article) |
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