Novel mutations in ADAMTS13 CUB domains cause abnormal pre-mRNA splicing and defective secretion of ADAMTS13.

Abstract

Hereditary thrombotic thrombocytopenic purpura (TTP) is an autosomal recessive thrombosis disorder, caused by loss-of-function mutations in ADAMTS13. Mutations in the CUB domains of ADAMTS13 are rare, and the exact mechanisms through which these mutations result in the development of TTP have not yet been fully elucidated. In this study, we identified two novel mutations in the CUB domains in a TTP family with an acceptor splice-site mutation (c.3569-1, G>A, intron 25) and a point missense mutation (c.3923, G>A, exon 28), resulting in a glycine to aspartic acid substitution (p.G1308D). In vitro splicing analysis revealed that the intronic mutation resulted in abnormal pre-mRNA splicing, and an in vitro expression assay revealed that the missense mutation significantly impaired ADAMTS13 secretion. Although both the patient and her brother displayed significantly reduced ADAMTS13 activity and increased levels of ultra-large VWF (ULVWF) multimers in plasma, only the female developed acute episodes of TTP. Our findings indicate the importance of the CUB domains for the protein stability and extracellular secretion of ADAMTS13.

• Authors: Yizhi Jiang, Dongping Huang, Yuji Kondo, Miao Jiang, Zhenni Ma, Lu Zhou, Jian Su, Xia Bai, Changgeng Ruan, Zhaoyue Wang, Lijun Xia
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 7 Pg. 4356-4361 (04 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 32073234 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Oklahoma Medical Research Foundation. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• RNA Precursors
• von Willebrand Factor
• ADAMTS13 Protein
• ADAMTS13 protein, human

Topics

• ADAMTS13 Protein (blood, genetics)
• Adult
• Female
• Humans
• Loss of Function Mutation (genetics)
• Mutation, Missense (genetics)
• Protein Multimerization (genetics)
• Protein Stability
• Purpura, Thrombotic Thrombocytopenic (blood, genetics, pathology)
• RNA Precursors (blood, genetics)
• RNA Splicing (genetics)
• von Willebrand Factor (genetics)