Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093, Nantes, France.
Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000, Nantes, France.
Eur J Hum Genet. 2020 Sep;28(9):1218-1230. doi: 10.1038/s41431-020-0583-2. Epub 2020 Feb 17.
Progeroid syndromes are a group of rare genetic disorders, which mimic natural aging. Unraveling the molecular defects in such conditions could impact our understanding of age-related syndromes such as Alzheimer's or cardiovascular diseases. Here we report a de novo heterozygous missense variant in the intermediate filament vimentin (c.1160 T > C; p.(Leu387Pro)) causing a multisystem disorder associated with frontonasal dysostosis and premature aging in a 39-year-old individual. Human vimentin p.(Leu387Pro) expression in zebrafish perturbed body fat distribution, and craniofacial and peripheral nervous system development. In addition, studies in patient-derived and transfected cells revealed that the variant affects vimentin turnover and its ability to form filaments in the absence of wild-type vimentin. Vimentin p.(Leu387Pro) expression diminished the amount of peripilin and reduced lipid accumulation in differentiating adipocytes, recapitulating key patient's features in vivo and in vitro. Our data highlight the function of vimentin during development and suggest its contribution to natural aging.
早衰综合征是一组罕见的遗传疾病，其表现类似于自然衰老。阐明这些疾病中的分子缺陷可能会影响我们对阿尔茨海默病或心血管疾病等与年龄相关的综合征的理解。在这里，我们报道了一个中间丝波形蛋白（c.1160T>C；p.(Leu387Pro)）的从头杂合错义变异，导致 39 岁个体出现多系统疾病，伴有额鼻发育不全和早衰。人类 vimentin p.(Leu387Pro)在斑马鱼中的表达扰乱了体脂肪分布以及颅面和外周神经系统的发育。此外，在患者来源的和转染的细胞中的研究表明，该变体影响波形蛋白周转及其在缺乏野生型波形蛋白的情况下形成纤维的能力。vimentin p.(Leu387Pro)的表达减少了外周蛋白的量，并减少了分化脂肪细胞中的脂质积累，在体内和体外重现了患者的关键特征。我们的数据强调了波形蛋白在发育过程中的功能，并表明其对自然衰老的贡献。
