A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3.
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.
University Department of Haematology, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom.
Megan S
MS
Sutherland
Anthony M
AM
Cumming
Mackenzie
M
Bowman
Paula H B
PH
Bolton-Maggs
Derrick J
DJ
Bowen
Peter W
PW
Collins
Charles R M
CR
Hay
Andrew M
AM
Will
Stephen
S
Keeney
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D004739:England / Q000453:epidemiology; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005799:Genes, Dominant; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D044465:White People / Q000235:genetics; D055815:Young Adult; D014842:von Willebrand Diseases / Q000145:classification / Q000208:ethnology / Q000235:genetics*; D014841:von Willebrand Factor / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D011993:Recombinant Fusion Proteins; D014841:von Willebrand Factor