期刊
HUMAN MUTATION
卷 43, 期 3, 页码 434-443出版社
WILEY-HINDAWI
DOI: 10.1002/humu.24322
关键词
male infertility; mutation; recessive inheritance; severe asthenozoospermia
资金
- National Key R&D Program of China [2021YFC2700901]
- Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT310002]
- National Natural Science Foundation of China [81901541, 82101682, 82171607]
- Research Fund of Anhui Institute of translational medicine [ZHYX2020A001]
Novel compound heterozygous mutations in SLC26A8 were identified in two unrelated infertile men with severe asthenozoospermia from nonconsanguineous Chinese families. These mutations are predicted to be disease-causing and may result in functional defects in the protein.
To investigate the genetic cause of male infertility characterized by severe asthenozoospermia, two unrelated infertile men with severe asthenozoospermia from nonconsanguineous Chinese families were enrolled, and whole exome sequencing were performed to identify the potential pathogenic mutations. Novel compound heterozygous mutations (NK062 III-1: c.290T>C, p.Leu97Pro; c.1664delT, p.Ile555Thrfs*11/NK038 III-1: c.212G>T, p.Arg71Leu; c.290T>C, p.Leu97Pro) in SLC26A8 were identified. All mutations were inherited from their heterozygous parents and are predicted to be disease-causing by sorts intolerant from tolerant, PolyPhen-2, Mutation Taster, and Combined Annotation Dependent Depletion. In silico mutant SLC26A8 models predict that mutations p.Leu97Pro and p.Arg71Leu cause changes in the alpha-helix, which may result in functional defects in the protein. Notably, heterozygous male carriers of each mutation in both families were able to reproduce naturally, which is inconsistent with previous reports. Ultrastructural analysis revealed severe asthenozoospermia associated with absence of the mitochondrial sheath and annulus in spermatozoa from both the probands, and both structural defects were verified by HSP60 and SEPT4 immunofluorescence analysis. SLC26A8 levels were significantly reduced in spermatozoa from patients harboring biallelic SLC26A8 mutations, and both patients achieved good prognosis following intracytoplasmic sperm injection. Our findings indicate that mutations in SLC26A8 could manifest as a recessive genetic cause of severe asthenozoospermia and male infertility.
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