Abstract
Yunis–Varon syndrome (YVS, MIM 216340) is a rare autosomal recessive disorder characterized by skeletal abnormalities and severe neurological impairment with vacuolation of the central nervous system, skeletal muscles and cartilages. Very recently, mutations of the FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing (Saccharomyces cerevisiae)) gene, which encodes a 5′-phosphoinositide phosphatase essential for endosome/lysosome function have been identified as the cause for YVS. Interestingly, FIG4 mutations were previously reported to be responsible for other neurodegenerative diseases such as autosomal recessive Charcot–Marie–Tooth disease type 4J and autosomal dominant amyotrophic lateral sclerosis/primary lateral sclerosis. We analyzed a YVS patient using whole-exome sequencing, and identified novel biallelic FIG4 mutations: c.1750+1delG and c.2284_2285delCT (p.S762Wfs*3). These two mutations were mutations supposed to have null function. To our knowledge, this is the second report of FIG4 mutations in YVS and our result supports the idea that biallelic null mutations of FIG4 cause YVS in human.
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References
Yunis, E. & Varon, H. Cleidocranial dysostosis, severe micrognathism, bilateral absence of thumbs and first metatarsal bone, and distal aphalangia: a new genetic syndrome. Am. J. Dis. Child. 134, 649–653 (1980).
Campeau, P. M., Lenk, G. M., Lu, J. T., Bae, Y., Burrage, L., Turnpenny, P. et al. Yunis–Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. Am. J. Hum. Genet. 92, 781–791 (2013).
Martyn, C. & Li, J. Fig4 deficiency: a newly emerged lysosomal storage disorder? Prog. Neurobiol. 101-102, 35–45 (2013).
Huotari, J. & Helenius, A. Endosome maturation. EMBO J. 30, 3481–3500 (2011).
Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M. et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am. J. Hum. Genet. 84, 85–88 (2009).
Zhang, X., Chow, C. Y., Sahenk, Z., Shy, M. E., Meisler, M. H. & Li, J. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain 131, 1990–2001 (2008).
Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J. et al. Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P(2) phosphatase FIG4. Brain 134, 1959–1971 (2011).
Garrett, C., Berry, A. C., Simpson, R. H. & Hall, C. M. Yunis–Varon syndrome with severe osteodysplasty. J. Med. Genet. 27, 114–121 (1990).
Walch, E., Schmidt, M., Brenner, R. E., Emons, D., Dame, C., Pontz, B. et al. Yunis–Varon syndrome: evidence for a lysosomal storage disease. Am. J. Med. Genet. 95, 157–160 (2000).
Dworzak, F., Mora, M., Borroni, C., Cornelio, F., Blasevich, F., Cappellini, A. et al. Generalized lysosomal storage in Yunis Varon syndrome. Neuromuscul. Disord. 5, 423–428 (1995).
Rabe, H., Brune, T., Rossi, R., Steinhorst, V., Jorch, G., Horst, J. et al. Yunis–Varon syndrome: the first case of German origin. Clin. Dysmorphol. 5, 217–222 (1996).
Pfeiffer, R. A., Diekmann, L. & Stock, H. J. Aplasia of the thumbs and great toes as the outstanding feature of Yunis and Varon syndrome. A new entity. A new observation. Ann. Genet. 31, 241–243 (1988).
Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K. et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448, 68–72 (2007).
de Leeuw, C. N. CMT4J: Charcot–Marie–Tooth disorder caused by mutations in FIG4. Clin. Genet. 73, 318–319 (2008).
Ikonomov, O. C., Sbrissa, D., Fligger, J., Delvecchio, K. & Shisheva, A. ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot–Marie–Tooth 4J disorder. J. Biol. Chem. 285, 26760–26764 (2010).
Acknowledgements
We thank the patient and her family for participating in this work. We also thank Ms S Sugimoto and K Takabe for their technical assistance. This work was supported by research grants from the Ministry of Health, Labour and Welfare (N Matsumoto and N Miyake), the Japan Science and Technology Agency (N Matsumoto), the Strategic Research Program for Brain Sciences (N Matsumoto) and a Grant-in-Aid for Scientific Research on Innovative Areas-(Transcription cycle)-from the Ministry of Education, Culture, Sports, Science and Technology of Japan (N Matsumoto), a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (H Saitsu, N Matsumoto and N Miyake), the Takeda Science Foundation (N Matsumoto and N Miyake) and the Hayashi Memorial Foundation for Female Natural Scientists (N Miyake).
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Nakajima, J., Okamoto, N., Shiraishi, J. et al. Novel FIG4 mutations in Yunis–Varon syndrome. J Hum Genet 58, 822–824 (2013). https://doi.org/10.1038/jhg.2013.104
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DOI: https://doi.org/10.1038/jhg.2013.104
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