Molecular defects in type 3 von Willebrand disease: updated results from 40 multiethnic patients.
Type 3 von Willebrand disease (VWD) is characterized by unmeasurable von Willebrand factor (VWF) levels in plasma and platelets and severe hemorrhagic symptoms. We have characterized at the molecular level a group of 40 patients (12 Italians, 14 Iranians, and 14 Indians) to evaluate genetic heterogeneity among these populations. Some of these patients have been previously investigated by us (mutations shown in italics); they are included in this study to provide a more comprehensive pattern of gene defects in type 3 VWD. Patients' DNA were first tested for more frequently reported mutations, then screened by single-strand conformation polymorphism and direct sequence analysis. Fifty gene defects were identified, of which 45 are novel. As expected most of these defects caused null alleles, 17 being nonsense mutations (Q218X, W222X, R365X, R373X, Y610X, W642X, E644X, Q706X, Q1311X, S1338X, Q1346X, Y1542X, R1659X, E1981X, E2129X, R2434X, and Q2544X), 12 small deletions (191delG, 276delT, 788del24, 2016del4, 2157delA, 2269delCT, 2435delC, 4092delAC, 6182delT, 7294delGT, 7683delT, and 8241del9), 4 small insertions (4414insC, 7130insC, 7137insT, and 7674insC), 8 possible splice site mutations (1110(-1)G-->A, 1946(-4)C-->T, 3108(+5)G-->A, 3379(+1)G-->A, 5053(+1)G-->A, 5170(+10)C-->T, 6977(-1)G-->C, and 7729(+7)C-->T), 8 candidate missense mutations (D47H, S85P, D141N, D141Y, C275S, C1071F, C2174G, and C2804Y), and 1 large gene deletion (exons 23-52). Only 2 of these patients have developed alloantibodies against VWF. This study extend our previous finding that mutations responsible for type 3 VWD are scattered throughout the entire VWF gene and that there is no founder effect in these three populations studied.
Baronciani
Luciano
L
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital and University of Milan, Italy. L.Baronciani@agora.stm.it
Cozzi
Giovanna
G
Canciani
Maria Teresa
MT
Peyvandi
Flora
F
Srivastava
Alok
A
Federici
Augusto B
AB
Mannucci
Pier Mannuccio
PM
D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D018703:Founder Effect; D006801:Humans; D007194:India; D007492:Iran; D007518:Isoantibodies / Q000097:blood; D007558:Italy; D017720:Molecular Epidemiology; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion; D014842:von Willebrand Diseases / Q000453:epidemiology / Q000208:ethnology*
D018389:Codon, Nonsense; D007518:Isoantibodies; D022821:RNA Splice Sites