Skip to Main content Skip to Navigation
Journal articles

Nonsense mediated decay of VWF mRNA subsequent to c.7674-7675insC mutation in type3 VWD patients.

Abstract : Von Willebrand disease (VWD), the most common genetic bleeding disorder, is caused by defects in Von Willebrand factor (VWF). Quantitative deficiencies of the protein lead to either VWD type3, the severe form of the disease or VWD type1 with milder clinical manifestation. Null alleles are the most common mutations in VWF gene causing type3. However, some of these mutations are not translated into the protein and are selectively degraded at mRNA level by nonsense-mediated decay (NMD) pathway. Here, we have studied a large VWD type3 pedigree with a premature termination codon (PTC) causing insertion mutation (c.7674-7675insC) in VWF exon 45. We further investigated the impact of the mutation on the VWF mRNA expression using a quantitative Real-time PCR assay and cDNA sequencing. The relative expression of the gene was significantly decreased in the patients' platelets (Mean ratio=0.03 (0.01-0.05), p=0.001) compared to their normal relatives. The heterozygote carriers of the mutation had lower than normal VWF mRNA levels (Mean ratio=0.62 (0.29-0.91), p=0.006). Direct sequencing of exon 45 on the platelet-derived cDNA in the carriers revealed only the wild-type allele confirming the decay of the mutation carrying allele. In conclusion, quantitative analysis of VWF gene expression showed that c.7674-7675insC mutation in VWF gene resulted in degradation of VWF mRNA via NMD. This pathway might play an important role in the pathogenesis of VWD characterized by quantitative deficiency of VWF due to reduced mRNA levels.
Document type :
Journal articles
Complete list of metadatas

Cited literature [22 references]  Display  Hide  Download

https://hal-riip.archives-ouvertes.fr/pasteur-00776080
Contributor : Reza Mahdian <>
Submitted on : Tuesday, January 15, 2013 - 8:18:26 AM
Last modification on : Wednesday, October 14, 2020 - 3:47:52 AM
Long-term archiving on: : Saturday, April 1, 2017 - 5:02:30 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Shirin Shahbazi, Farzad Baniahmad, Mahshid Zakiani-Roudsari, Mozhgan Raigani, Reza Mahdian. Nonsense mediated decay of VWF mRNA subsequent to c.7674-7675insC mutation in type3 VWD patients.. Blood Cells, Molecules and Diseases, Elsevier, 2012, 49 (1), pp.48-52. ⟨10.1016/j.bcmd.2012.03.007⟩. ⟨pasteur-00776080⟩

Share

Metrics

Record views

120