Open AccessNovel mutations in ADAMTS13 CUB domains cause abnormal pre‐mRNA splicing and defective secretion of ADAMTS13
Author(s) -
Jiang Yizhi,
Huang Dongping,
Kondo Yuji,
Jiang Miao,
Ma Zhenni,
Zhou Lu,
Su Jian,
Bai Xia,
Ruan Changgeng,
Wang Zhaoyue,
Xia Lijun
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15025
Subject(s) - missense mutation , adamts13 , rna splicing , exon , mutation , exon skipping , intron , splice site mutation , microbiology and biotechnology , point mutation , splice , chemistry , genetics , biology , thrombotic thrombocytopenic purpura , alternative splicing , gene , platelet , immunology , rna
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.