Abstract
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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References
Gruenbaum Y, Foisner R. Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annu Rev Biochem. 2015;84:131–64.
Bouameur JE, Magin TM. Lessons from animal models of cytoplasmic intermediate filament proteins. Subcell Biochem. 2017;82:171–230.
Chernyatina AA, Guzenko D, Strelkov SV. Intermediate filament structure: the bottom-up approach. Curr Opin Cell Biol. 2015;32:65–72.
Cheng F, Eriksson JE. Intermediate filaments and the regulation of cell motility during regeneration and wound healing. Cold Spring Harb Perspect Biol. 2017;9:pii: a022046.
Ma AS, Grigg JR, Ho G, Prokudin I, Farnsworth E, Holman K, et al. Sporadic and familial congenital cataracts: mutational spectrum and new diagnoses using next-generation sequencing. Hum Mutat. 2016;37:371–84.
Muller M, Bhattacharya SS, Moore T, Prescott Q, Wedig T, Herrmann H, et al. Dominant cataract formation in association with a vimentin assembly disrupting mutation. Hum Mol Genet. 2009;18:1052–7.
Bornheim R, Muller M, Reuter U, Herrmann H, Bussow H, Magin TM. A dominant vimentin mutant upregulates Hsp70 and the activity of the ubiquitin-proteasome system, and causes posterior cataracts in transgenic mice. J Cell Sci. 2008;121:3737–46.
Wilhelmsson U, Stillemark-Billton P, Boren J, Pekny M. Vimentin is required for normal accumulation of body fat. Biol Chem. 2019;400:1157–62.
Chen M, Puschmann TB, Marasek P, Inagaki M, Pekna M, Wilhelmsson U, et al. Increased neuronal differentiation of neural progenitor cells derived from phosphovimentin-deficient mice. Mol Neurobiol. 2018;55:5478–89.
Tanaka H, Goto H, Inoko A, Makihara H, Enomoto A, Horimoto K, et al. Cytokinetic failure-induced tetraploidy develops into aneuploidy, triggering skin aging in phosphovimentin-deficient mmice. J Biol Chem. 2015;290:12984–98.
Matsuyama M, Tanaka H, Inoko A, Goto H, Yonemura S, Kobori K, et al. Defect of mitotic vimentin phosphorylation causes microophthalmia and cataract via aneuploidy and senescence in lens epithelial cells. J Biol Chem. 2013;288:35626–35.
Olive M, Armstrong J, Miralles F, Pou A, Fardeau M, Gonzalez L, et al. Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene. Neuromuscul Disord. 2007;17:443–50.
Nelson WJ, Traub P. Proteolysis of vimentin and desmin by the Ca2+-activated proteinase specific for these intermediate filament proteins. Mol Cell Biol. 1983;3:1146–56.
Fischer S, Vandekerckhove J, Ampe C, Traub P, Weber K. Protein-chemical identification of the major cleavage sites of the Ca2+ proteinase on murine vimentin, the mesenchymal intermediate filament protein. Biol Chem Hoppe Seyler 1986;367:1147–52.
Schlegel A, Stainier DY. Microsomal triglyceride transfer protein is required for yolk lipid utilization and absorption of dietary lipids in zebrafish larvae. Biochemistry 2006;45:15179–87.
Sarjeant K, Stephens JM. Adipogenesis. Cold Spring Harb Perspect Biol. 2012;4:a008417.
Tong Q, Tsai J, Hotamisligil GS. GATA transcription factors and fat cell formation. Drug N Perspect. 2003;16:585–8.
Heid H, Rickelt S, Zimbelmann R, Winter S, Schumacher H, Dorflinger Y, et al. On the formation of lipid droplets in human adipocytes: the organization of the perilipin-vimentin cortex. PLoS ONE 2014;9:e90386.
Franke WW, Hergt M, Grund C. Rearrangement of the vimentin cytoskeleton during adipose conversion: formation of an intermediate filament cage around lipid globules. Cell 1987;49:131–41.
Brasaemle DL, Subramanian V, Garcia A, Marcinkiewicz A, Rothenberg A. Perilipin A and the control of triacylglycerol metabolism. Mol Cell Biochem. 2009;326:15–21.
Omary MB. “IF-pathies”: a broad spectrum of intermediate filament-associated diseases. J Clin Invest. 2009;119:1756–62.
Jackson BW, Grund C, Winter S, Franke WW, Illmensee K. Formation of cytoskeletal elements during mouse embryogenesis. II. Epithelial differentiation and intermediate-sized filaments in early postimplantation embryos. Differentiation 1981;20:203–16.
Franke WW, Grund C, Kuhn C, Jackson BW, Illmensee K. Formation of cytoskeletal elements during mouse embryogenesis. III. Primary mesenchymal cells and the first appearance of vimentin filaments. Differentiation 1982;23:43–59.
Goldfarb LG, Dalakas MC. Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest. 2009;119:1806–13.
Homberg M, Magin TM. Beyond expectations: novel insights into epidermal keratin function and regulation. Int Rev Cell Mol Biol. 2014;311:265–306.
Gass JK, Wilson NJ, Smith FJ, Lane EB, McLean WH, Rytina E, et al. Steatocystoma multiplex, oligodontia and partial persistent primary dentition associated with a novel keratin 17 mutation. Br J Dermatol. 2009;161:1396–8.
Colucci-Guyon E, Portier MM, Dunia I, Paulin D, Pournin S, Babinet C. Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell 1994;79:679–94.
Boyne LJ, Fischer I, Shea TB. Role of vimentin in early stages of neuritogenesis in cultured hippocampal neurons. Int J Dev Neurosci. 1996;14:739–48.
Yabe JT, Chan WK, Wang FS, Pimenta A, Ortiz DD, Shea TB. Regulation of the transition from vimentin to neurofilaments during neuronal differentiation. Cell Motil Cytoskeleton. 2003;56:193–205.
Jiang SX, Slinn J, Aylsworth A, Hou ST. Vimentin participates in microglia activation and neurotoxicity in cerebral ischemia. J Neurochem. 2012;122:764–74.
Triolo D, Dina G, Taveggia C, Vaccari I, Porrello E, Rivellini C, et al. Vimentin regulates peripheral nerve myelination. Development. 2012;139:1359–67.
Larsson A, Wilhelmsson U, Pekna M, Pekny M. Increased cell proliferation and neurogenesis in the hippocampal dentate gyrus of old GFAP(−/−)Vim(−/−) mice. Neurochem Res. 2004;29:2069–73.
Lieber JG, Evans RM. Disruption of the vimentin intermediate filament system during adipose conversion of 3T3-L1 cells inhibits lipid droplet accumulation. J Cell Sci. 1996;109:3047–58.
Capetanaki Y, Smith S, Heath JP. Overexpression of the vimentin gene in transgenic mice inhibits normal lens cell differentiation. J Cell Biol. 1989;109:1653–64.
Wang Y, Ostlund C, Choi JC, Swayne TC, Gundersen GG, Worman HJ. Blocking farnesylation of the prelamin A variant in Hutchinson-Gilford progeria syndrome alters the distribution of A-type lamins. Nucleus. 2012;3:452–62.
Tajan M, Paccoud R, Branka S, Edouard T, Yart A. The RASopathy family: consequences of germline activation of the RAS/MAPK pathway. Endocr Rev. 2018;39:676–700.
Acknowledgements
We thank Dr Hans Heid and Professor Harald Herrmann (German Cancer Research Center, Heidelberg, Germany) for providing anti-perilipin antibody and human vimentin cDNA, and Strelkov SV (KU Leuven, Leuven, Belgium) for crosschecking the mutant structure model. We are grateful to the staff of the zebrafish (in particular Sandrine Geschier) and imaging facilities of the Institut de Génétique et de Biologie Moléculaire et Cellulaire. TMM dedicates this work to Prof. Werner W. Franke on the occasion of his 80th birthday.
Funding
This work was partially supported by the DFG (Deutsche Forschungsgemeinschaft) (MA1316–15, MA1316–17, MA1316–19, MA1316–21, INST 268/230–1) to TMM and J-EB (MA 1316/15–2), the French Programme Investissements d’Avenir (ANR-10-IDEX-0002–02, ANR-10-LABX-0030-INRT) to CG, and ROTARY Club des Sables d’Olonne to BI. GH is supported by a PhD fellowship (ANR-10-LABX-0030-INRT). DK was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC-StG2013 337713 DarkSide starting grant.
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BC, J-EB, CG, TMM, and BI co-designed the study and wrote the manuscript. BC designed and performed exome analysis. J-EB designed and performed the experiments involving mammalian cells and sequence alignments. CG and GH designed and performed the zebrafish experiments. SP, DK, XL, TB, and SK performed molecular biology experiments. PB and BI performed clinical evaluation of the patient. LD, AC, and KS performed patient’s cells reprogramming.
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Cogné, B., Bouameur, JE., Hayot, G. et al. A dominant vimentin variant causes a rare syndrome with premature aging. Eur J Hum Genet 28, 1218–1230 (2020). https://doi.org/10.1038/s41431-020-0583-2
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DOI: https://doi.org/10.1038/s41431-020-0583-2
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