Von Willebrand disease investigated by two novel RFLPs

Abstract

Two partial cDNAs for von Willebrand factor (vWF) were used to investigate gene lesions and restriction fragment length polymorphisms (RFLPs) in vW disease (vWd) and normal controls. No gene alteration was detected but two TaqI RFLPs, likely to be intronic and originating from point mutations, were found in the 3' part of vWF gene. The two TaqI RFLPs, identified by the same probe, are informative in approximately 50% of the subjects. Used in combination with two other known RFLPs, they define several haplotypes similarly distributed in vWd and normals. Linkage disequilibrium between loci identified by the RFLPs is present. In a family study the RFLP patterns demonstrate homozygosity for the affected vWF gene in a severe (type III) patient and identify several heterozygous subjects. The RFLPs analysis has been related to the haemostatic values and multimer distribution. In two of the four unrelated patients with severe vWd examined the RFLPs study indicates double heterozygosity for the affected vWF genes.

The inheritance and molecular genetics of von Willebrand's disease

“…Homozygosity for a partial vWF gene deletion of exon 42 in an another severe type I11 vWD patient was demonstrated by Peake et al [106]. N o deletions were found in most type 111 vWD patients [95,97,107], so most defects will probably be single nucleotide substitutions or small deletions and insertions. However, no specific region o r functional domain of the vWF was predicted to be responsible for the quantitative defect.…”

The molecular biology of von Willebrand disease

“…Very few mutations or molecular mechanisms have been described to account for the autosomal dominant mode of inheritance seen in classical type 1 VWD. A number of gene linkage studies in affected families support linkage of VWD to the VWF locus (Bahnak et al., 1988; Bernardi et al., 1988; Bignell et al., 1990; Caekebeke‐Peerlinck et al., 1990; Peake et al., 1990; Standen et al., 1990), although Nichols & Ginsburg (1997) pointed out that these linkage studies did not attain statistical significance for each individual family studied. Casana et al.…”

Carrier Detection in Severe (Type III) von Willebrand Disease Using Two Intragenic Restriction Fragment Length Polymorphisms

“…The cloning of the vWF cDNA has allowed studies of the genetic defects in vWD (5)(6)(7)(8). These studies have demonstrated patients who exhibit complete or partial deletions in both chromosomes (9)(10)(11), complete deletion in one chromosome combined with an undefined defect in the other chromosome (11) and a large group of patients who show no alteration in the gene as demonstrated by Southern blot analysis with cDNA probes (9,12). In the latter group, it is necessary to develop an extensive number of restriction fragment length polymorphisms (RFLPs) that can be used as a genetic marker for segregation studies in families affected with severe vWD.…”