Abstract
Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder characterized by unique, bilateral neuropathological findings in brainstem, basal ganglia, cerebellum and spinal cord. LS is genetically heterogeneous, with the majority of the causative genes affecting mitochondrial malfunction, and many cases still remain unsolved. Here, we report male sibs affected with LS showing ketonemia, but no marked elevation of lactate and pyruvate. To identify their genetic cause, we performed whole exome sequencing. Candidate variants were narrowed down based on autosomal recessive and X-linked recessive models. Only one hemizygous missense mutation (c.665G>C, p.W222S) in glycogenin-2 (GYG2) (isoform a: NM_001079855) in both affected sibs and a heterozygous change in their mother were identified, being consistent with the X-linked recessive trait. GYG2 encodes glycogenin-2 (GYG2) protein, which plays an important role in the initiation of glycogen synthesis. Based on the structural modeling, the mutation can destabilize the structure and result in protein malfunctioning. Furthermore, in vitro experiments showed mutant GYG2 was unable to undergo the self-glucosylation, which is observed in wild-type GYG2. This is the first report of GYG2 mutation in human, implying a possible link between GYG2 abnormality and LS.
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Acknowledgments
We thank all the patients and their families for participating in this work. We deeply appreciate Dr. Toshiyuki Fukao, who is the professor of Department of Pediatrics, Graduate School of Medicine, Gifu University, for the enzyme assay for 3-ketothiolase deficiency and succinyl-CoA:3-oxoacid CoA transferase. We would like to thank Dr. Yasushi Okazaki at Research Center for Genomic Medicine, Saitama Medical University for helpful discussion. We also thank Ms. Y. Yamashita, S. Sugimoto and K. Takabe for their technical assistance. This work was supported by research grants from the Ministry of Health, Labour, and Welfare (H. Saitsu, N. Matsumoto and N. Miyake), the Japan Science and Technology Agency (N. Matsumoto), the Strategic Research Program for Brain Sciences (to N. Matsumoto), 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 the Japan Society for the Promotion of Science (to N. Matsumoto), a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science (H. Saitsu and N. Miyake), a grant from the 2012 Strategic Research Promotion of Yokohama City University (N. Matsumoto), and research grants from the Japan Epilepsy Research Foundation (H. Saitsu) and the Takeda Science Foundation (N. Matsumoto and N. Miyake).
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Imagawa, E., Osaka, H., Yamashita, A. et al. A hemizygous GYG2 mutation and Leigh syndrome: a possible link?. Hum Genet 133, 225–234 (2014). https://doi.org/10.1007/s00439-013-1372-6
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DOI: https://doi.org/10.1007/s00439-013-1372-6