Multiple Substitutions in the von Willebrand Factor Gene that Mimic the Pseudogene Sequence

• Published in: Proceedings of the National Academy of Sciences - PNAS 1994-03, Vol.91 (6), p.2221-2224
• Main Authors: Jeroen C. J. Eikenboom, Vink, Tom, Briet, Ernest, Sixma, Jan J., Reitsma, Pieter H.
• Format: Article
• Language: English
• Subjects: Alleles; Analytical, structural and metabolic biochemistry; Base Sequence; Biological and medical sciences; Complementary DNA; Disease; DNA; DNA Mutational Analysis; Exons; Fundamental and applied biological sciences. Psychology; gene conversion; Genes; Genetic mutation; Genetics; Glycoproteins; Humans; man; Molecular Sequence Data; mucleotides; Mutation; Nucleotides; Polymerase chain reaction; Proteins; Pseudogenes; RNA; substitution; von Willebrand Diseases - genetics; von Willebrand factor; von Willebrand Factor - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.6.2221

We have analyzed a type IIB and a type I von Willebrand disease family for the presence of mutations in the region coding for the glycoprotein Ib binding domain of the von Willebrand factor. Since this sequence is also present in the highly homologous von Willebrand factor pseudogene, we have studied genomic DNA as well as cDNA, which was produced from RNA isolated from endothelial cells or platelets. In both families, we have detected multiple consecutive nucleotide substitutions in the 5' end of exon 28 that result in a sequence identical to the von Willebrand factor pseudogene. These substitutions were also found in cDNA, which proves that they are present in the active gene. The occurrence of multiple adjacent substitutions that exactly reflect a part of the sequence of the von Willebrand factor pseudogene is difficult to reconcile with sequential single mutational events. We therefore hypothesize that each of these multiple substitutions arose from one recombinational event between gene and pseudogene.