SLC26A4 C.317C > A变异:功能分析和患者来源的诱导多能干细胞发育。

IF 1.5 4区 医学 Q4 GENETICS & HEREDITY
Yijing Li, Tao Sun, Sang Hu, Hongen Xu, Teng Zhang, Jinlong Liu, Shuangshuang Lu, Bing Wang, Guo Dan
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引用次数: 0

摘要

背景:SLC26A4是遗传性听力损失的第二大常见原因。该基因主要含有致病性变异,包括剪接、无义和错义。虽然错义变异相对常见,但它们对蛋白质功能的具体影响尚不清楚。因此,迫切需要建立一个体外系统来研究这些变异如何影响SLC26A4蛋白的功能。方法:通过基因检测确定患者潜在基因变异的具体类型。在此之后,我们使用质粒转染来评估变异对蛋白质表达水平和蛋白质亚细胞定位的影响。然后,我们通过仙台病毒介导的转导将先证者的外周血单个核细胞(PBMCs)转化为诱导多能干细胞(iPSCs)。结果:先证者携带复合杂合变异体SLC26A4 c.919-2A > G和c.317C > A。c.317C > A变异显著降低SLC26A4 mRNA及其编码蛋白的表达水平。此外,它还导致蛋白质以聚集体的形式在细胞质中积累。我们成功地将先证者的外周血单个核细胞重编程为诱导多能干细胞(iPSCs),并证实这些iPSCs保留了其多能性、分化潜力和遗传完整性。结论:这些结果为SLC26A4基因变异导致听力损失的机制提供了重要的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
SLC26A4 C.317C > A Variant: Functional Analysis and Patient-Derived Induced Pluripotent Stem Line Development.

Background: SLC26A4 is the second most common cause of hereditary hearing loss worldwide. This gene predominantly harbors pathogenic variants, including splice, nonsense, and missense. Although missense variants are relatively common, their specific effects on protein function remain unclear. Consequently, there is an urgent need to establish an in vitro system to investigate how these variants impact SLC26A4 protein function.

Methods: Genetic testing was conducted to determine the specific types of underlying genetic variants in patients. Following this, we employed plasmid transfection to evaluate the effects of the variants on both protein expression levels and the protein's subcellular localization. Thereafter, we transformed peripheral blood mononuclear cells (PBMCs) from the proband into induced pluripotent stem cells (iPSCs) through Sendai virus-mediated transduction.

Results: Genetic testing revealed that the proband carried compound heterozygous variants: SLC26A4 c.919-2A > G and c.317C > A. The c.317C > A variant markedly decreased the expression levels of SLC26A4 mRNA and its encoded protein. Additionally, it led to the protein's accumulation in the cytoplasm as aggregates. We successfully reprogrammed peripheral blood mononuclear cells from the proband into induced pluripotent stem cells (iPSCs) and verified that these iPSCs retained their pluripotency, differentiation potential, and genetic integrity.

Conclusion: These results provide important insights into the mechanisms by which SLC26A4 gene variants lead to hearing loss.

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来源期刊
Molecular Genetics & Genomic Medicine
Molecular Genetics & Genomic Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
4.20
自引率
0.00%
发文量
241
审稿时长
14 weeks
期刊介绍: Molecular Genetics & Genomic Medicine is a peer-reviewed journal for rapid dissemination of quality research related to the dynamically developing areas of human, molecular and medical genetics. The journal publishes original research articles covering findings in phenotypic, molecular, biological, and genomic aspects of genomic variation, inherited disorders and birth defects. The broad publishing spectrum of Molecular Genetics & Genomic Medicine includes rare and common disorders from diagnosis to treatment. Examples of appropriate articles include reports of novel disease genes, functional studies of genetic variants, in-depth genotype-phenotype studies, genomic analysis of inherited disorders, molecular diagnostic methods, medical bioinformatics, ethical, legal, and social implications (ELSI), and approaches to clinical diagnosis. Molecular Genetics & Genomic Medicine provides a scientific home for next generation sequencing studies of rare and common disorders, which will make research in this fascinating area easily and rapidly accessible to the scientific community. This will serve as the basis for translating next generation sequencing studies into individualized diagnostics and therapeutics, for day-to-day medical care. Molecular Genetics & Genomic Medicine publishes original research articles, reviews, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented.
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