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.
Sutherland
Megan S
MS
University Department of Haematology, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom.
Cumming
Anthony M
AM
Bowman
Mackenzie
M
Bolton-Maggs
Paula H B
PH
Bowen
Derrick J
DJ
Collins
Peter W
PW
Hay
Charles R M
CR
Will
Andrew M
AM
Keeney
Stephen
S
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