Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 28, Issue 9, Pages 1218-1230Publisher
SPRINGERNATURE
DOI: 10.1038/s41431-020-0583-2
Keywords
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Funding
- DFG (Deutsche Forschungsgemeinschaft) [MA1316-15, MA1316-17, MA1316-19, MA1316-21, INST 268/230-1, MA 1316/15-2]
- French Programme Investissements d'Avenir [ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT]
- ROTARY Club des Sables d'Olonne
- European Research Council under the European Union [StG2013 337713]
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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.
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