Biomedical subjects

E W Murray

Publications and source records attributed to E W Murray.

9 recordsLinked to original sources

PubMed1992

Germ-line mosaicism for a valine-to-methionine substitution at residue 553 in the glycoprotein Ib-binding domain of von Willebrand factor, causing type IIB von Willebrand disease.

The origin of new single-gene mutations resulting in inherited disease is an issue which may be at least partially resolved by our enhanced ability to detect these changes. In this report we describe the identification of a missense mutation at codon 553 (guanine to adenine) in the von Willebrand factor (vWf) gene in affected members of a family with type IIB von Willebrand's disease (vWd). We found no evidence for this substitution in 190 normal vWf genes. The encoded substitution of a methionine for a valine at this residue is nonconservative in nature and has affected a vWf protein region which has been shown to facilitate binding to the platelet receptor glycoprotein Ib. In patients with type IIB vWd this interaction is characteristically increased in affinity. This mutation has also recently been recorded in four other type IIB vWd families. Thus, there is strong circumstantial evidence to incriminate this substitution as the disease causing mutation in this family. As further supporting evidence for this claim, we have shown by vWf polymorphism analysis that the mutation originated in a vWf gene transmitted from a phenotypically normal grandfather. Analysis of the sperm from this individual showed that approximately 5% of the germ line contained the mutant 553 sequence. These results confirm (1) that the candidate type IIB vWd mutation in this family occurred at some time during the development of the germ line of the grandfather and presumably was related to a mitotic cell division and (2) that, as a result, he is a low-level germ-line mosaic for the mutation.

Autoradiography↗

PubMed1991

Cosegregation of von Willebrand factor gene polymorphisms and possible germinal mosaicism in type IIB von Willebrand disease.

Recent reports of the mutations resulting in von Willebrand disease (vWD) have indicated that some cases of type IIA vWD are caused by single nucleotide substitutions in the gene encoding von Willebrand factor (vWF). However, the molecular pathogenesis of type IIB vWD remains unresolved and, with the complex posttranslational processing required for fully functional vWF, the mutations responsible for this phenotype may occur at loci other than the vWF gene. This study has used six intragenic vWF polymorphisms to assess the linkage of type IIB vWD to this gene in three families (48 individuals). The results of these studies indicate that there is significant linkage between the vWF gene and the type IIB phenotype (logarithm of the odds ratio of 7.2 at theta = 0), suggesting that the mutations responsible for this disorder frequently occur at this locus. Results from one of these families indicates that the disorder has been transmitted from an unaffected parent to two children who have inherited the same vWF gene as seven unaffected siblings. This finding is suggestive of the presence of germinal mosaicism for the mutation in the father.

Base Sequence↗

PubMed1991

Recurring mutations at CpG dinucleotides in the region of the von Willebrand factor gene encoding the glycoprotein Ib binding domain, in patients with type IIB von Willebrand's disease.

The mutant von Willebrand factor (vWf) molecule in type IIB von Willebrand's disease (vWd) has an increased binding affinity for the platelet receptor glycoprotein Ib (GpIb). In previous studies we have confirmed genetic linkage of this phenotype to the vWf gene and in this report we document three recurring missense mutations in the region of the gene that encodes the GpIb binding domain. Two families with type IIB vWd were found to have an arginine to tryptophan substitution at residue 543, three families had a valine to methionine substitution at residue 553, and one kindred had an arginine to glutamine change at amino acid 578. None of these sequence changes were found in 200 normal vWf genes and within each of the six families the mutations were only found in affected subjects. This is strong circumstantial evidence in support of these substitutions representing the disease causing mutations in these families. All three of these substitutions have occurred at CpG dinucleotide sequences, and their polymorphic associations indicate that they represent recurring new mutations. Missense mutations at these sites may represent the underlying genetic pathology in a large number of type IIB vWd families.

Alleles↗

PubMed1979