In-frame deletion of von Willebrand factor A domains in a dominant type of von Willebrand disease.
von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, is very heterogeneous and has been classified into several subtypes. Missense mutations have been found to be responsible for the dominant type II vWD, characterized by qualitative abnormalities affecting von Willebrand factor (vWF) function. The breakpoints of a heterozygous vWF gene deletion (31 Kb), occurring 'de novo' in a patient with a variant of type II vWD, were localized to introns 25 and 34 and sequenced. An Alu repeat in intron 25 was interrupted between the transcriptional boxes A and B. The new junction present in the abnormal von Willebrand factor mRNA was sequenced after reverse transcription of platelet RNA. The codon 1104 (Cys) is followed in frame by the mutated codon 1926 (Cys to Arg), thus removing the complete A domains, found in a wide variety of genes and characterized by independent assembly 'in vitro'. We propose that the abnormal vWF, which carries intact protein domains responsible for vWF dimer and multimer formation, makes ineffective interactions with the normal molecules in the biosynthetic process, causing the dominant type II phenotype through a novel mechanism.
Centro Studi Biochimici delle Patologie del Genoma Umano, Università di Ferrara, Italy.
F
F
Bernardi
P
P
Patracchini
D
D
Gemmati
M
M
Pinotti
C
C
Schwienbacher
G
G
Ballerini
G
G
Marchetti
D001483:Base Sequence; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D005799:Genes, Dominant; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D017384:Sequence Deletion; D014842:von Willebrand Diseases / Q000145:classification / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics*
D012333:RNA, Messenger; D014841:von Willebrand Factor; D004247:DNA