A novel type 2A von Willebrand factor mutation located at the last nucleotide of exon 26 (3538G>A) causes skipping of 2 nonadjacent exons.

Blood
Paula D JamesD Lillicrap

Abstract

In this manuscript, we describe a case of type 2A von Willebrand disease (VWD) caused by the novel heterozygous G>A transition at nucleotide 3538, which should result in the putative, nonconservative substitution of G1180R. This mutation was reproduced by site-directed mutagenesis; however, the recombinant mutant protein was efficiently secreted from cells and assembled correctly into multimers. Because the substitution is located at the last nucleotide of exon 26, the patient's platelet von Willebrand factor (VWF) mRNA was analyzed and 3 transcripts were observed: the normal transcript without the 3538G>A transition, a transcript with the in-frame deletion of exon 26, and a transcript with the in-frame deletions of exons 23 and 26. These deletion VWF cDNA constructs were created and the resulting recombinant proteins were analyzed following transfection into COS-7 cells. Cotransfection results demonstrate that the exon-skipped transcripts led to intracellular retention, and the levels of VWF antigen (VWF:Ag) produced by these constructs were as follows: del23/26<del26< G1180R<or=wild type. The homozygous exon-skipped transcripts show the presence of only the lowest molecular weight multimers. The G>A transition at nucleotide (...Continue Reading

References

Oct 21, 1991·Nucleic Acids Research·D K Lahiri, J I Nurnberger
Aug 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·J A DentZ M Ruggeri
Oct 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·J E SadlerE W Davie
Dec 1, 1993·The Journal of Pediatrics·E J WernerT C Abshire
Aug 25, 2000·Molecular and Cellular Biology·W G Fairbrother, L A Chasin
May 10, 2001·Current Opinion in Cell Biology·C L Will, R Lührmann
Jun 26, 2001·RNA·B R GraveleyT Maniatis
Apr 5, 2002·Nature·Tom Maniatis, Robin Reed
May 22, 2003·Genes, Chromosomes & Cancer·Kathleen ClaesLudwine Messiaen
Jun 26, 2003·Nucleic Acids Research·Michael Zuker
Jun 26, 2003·Nucleic Acids Research·Luca CartegniAdrian R Krainer

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Citations

Sep 9, 2005·Nucleic Acids Research·Jinhua WangMichael Q Zhang
Apr 23, 2010·Blood Reviews·Anne C Goodeve
Jul 25, 2009·Journal of Thrombosis and Haemostasis : JTH·E BerberD Lillicrap
Jun 30, 2011·Journal of Thrombosis and Haemostasis : JTH·J D RobertsonP D James

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