Exome sequencing reveals a novel MFN2 missense mutation in a Chinese family with Charcot‑Marie‑Tooth type 2A

You,Yi; Wang,Xiaodong; Li,Shan; Zhao,Xiuli; Zhang,Xue

doi:10.3892/etm.2018.6513

Exome sequencing reveals a novel MFN2 missense mutation in a Chinese family with Charcot‑Marie‑Tooth type 2A

Authors:
- Yi You
- Xiaodong Wang
- Shan Li
- Xiuli Zhao
- Xue Zhang
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Affiliations: Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, P.R. China, Department of Paediatric Orthopaedics, The Children's Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
Published online on: July 24, 2018 https://doi.org/10.3892/etm.2018.6513
Pages: 2281-2286
Copyright: © You et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Charcot‑Marie‑Tooth (CMT) is a group of inherited peripheral neuropathies. To date, mutations in >80 genes are reportedly associated with CMT. Protein mitofusin 2 encoded by MFN2 serves an essential role in mitochondrial fusion and regulation of apoptosis, which has previously been reported to be highly associated with an axonal form of neuropathy (CMT2A). In the present study, a large Chinese family with severe CMT was reported and a genetic analysis of the disease was performed. A detailed physical examination for CMT was performed in 13 family members and electrophysiological examinations were performed in 3 affected family members. Whole‑exome sequencing was performed on the proband, and the suspected variants were identified by Sanger sequencing. The pathogenicity of mutation was verified by restriction fragment length polymorphism analysis in the family followed by a bioinformatics analysis. A novel c.1190G>C; p.(R397P) mutation in the MFN2 gene was identified in the proband, and co‑segregated between genotype and phenotype in the family. The substituted amino acid changed the hydrophobicity and charge characteristics of the mitofusin 2 coiled‑coiled domain; thus it may affect its biological function. In summary, a novel pathogenic mutation was identified in a Chinese family with CMT, which expands the phenotypic and mutational spectrum of CMT2A, and provides evidence for prenatal interventions and more precise pharmacological treatments to this family.

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1	Kazamel M and Boes CJ: Charcot marie tooth disease (CMT): Historical perspectives and evolution. J Neurol. 262:801–805. 2015. View Article : Google Scholar : PubMed/NCBI
2	Timmerman V, Strickland AV and Züchner S: Genetics of charcot-marie-tooth (CMT) disease within the frame of the human genome project success. Genes (Basel). 5:13–32. 2014. View Article : Google Scholar : PubMed/NCBI
3	Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, et al: Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 36:449–451. 2004. View Article : Google Scholar : PubMed/NCBI
4	Tufano M, Cappuccio G, Terrone G, Manganelli F, Pisciotta C, Geroldi A, Capponi S and Del Giudice E: Early onset Charcot-Marie-Tooth neuropathy type 2A and severe developmental delay: Expanding the clinical phenotype of MFN2-related neuropathy. J Peripher Nerv Syst. 20:415–418. 2015. View Article : Google Scholar : PubMed/NCBI
5	Stuppia G, Rizzo F, Riboldi G, Del Bo R, Nizzardo M, Simone C, Comi GP, Bresolin N and Corti S: MFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives. J Neurol Sci. 356:7–18. 2015. View Article : Google Scholar : PubMed/NCBI
6	Siskind CE, Panchal S, Smith CO, Feely SM, Dalton JC, Schindler AB and Krajewski KM: A review of genetic counseling for Charcot Marie Tooth disease (CMT). J Genet Couns. 22:422–436. 2013. View Article : Google Scholar : PubMed/NCBI
7	Xie Y, Li X, Liu L, Hu Z, Huang S, Zhan Y, Zi X, Xia K, Tang B and Zhang R: MFN2-related genetic and clinical features in a cohort of Chinese CMT2 patients. J Peripher Nerv Syst. 21:38–44. 2016. View Article : Google Scholar : PubMed/NCBI
8	Wei X, Ju X, Yi X, Zhu Q, Qu N, Liu T, Chen Y, Jiang H, Yang G, Zhen R, et al: Identification of sequence variants in genetic disease-causing genes using targeted next-generation sequencing. PLoS One. 6:e295002011. View Article : Google Scholar : PubMed/NCBI
9	Wang B, Zheng Z, Wang Z, Zhang X, Yang H, Cai H and Fu Q: A novel missense mutation of TNNI2 in a Chinese family cause distal arthrogryposis type 1. Am J Med Genet A. 170A:135–141. 2016. View Article : Google Scholar : PubMed/NCBI
10	Jiang Y, Pan J, Guo D, Zhang W, Xie J, Fang Z, Guo C, Fang Q, Jiang W and Guo Y: Two novel mutations in the PPIB gene cause a rare pedigree of osteogenesis imperfecta type IX. Clin Chim Acta. 469:111–118. 2017. View Article : Google Scholar : PubMed/NCBI
11	Jiang M, Zhao X, Han W, Bian C, Li X, Wang G, Ao Y, Li Y, Yi D, Zhe Y, et al: A novel deletion in TNNI2 causes distal arthrogryposis in a large Chinese family with marked variability of expression. Hum Genet. 120:238–242. 2006. View Article : Google Scholar : PubMed/NCBI
12	Cao YL, Meng S, Chen Y, Feng JX, Gu DD, Yu B, Li YJ, Yang JY, Liao S, Chan DC and Gao S: MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion. Nature. 542:372–376. 2017. View Article : Google Scholar : PubMed/NCBI
13	Harel T and Lupski JR: Charcot-Marie-Tooth disease and pathways to molecular based therapies. Clin Genet. 86:422–431. 2014. View Article : Google Scholar : PubMed/NCBI
14	Zimoń M, Battaloğlu E, Parman Y, Erdem S, Baets J, De Vriendt E, Atkinson D, Almeida-Souza L, Deconinck T, Ozes B, et al: Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach. Neurogenetics. 16:33–42. 2015. View Article : Google Scholar : PubMed/NCBI
15	Kostera-Pruszczyk A, Kosinska J, Pollak A, Stawinski P, Walczak A, Wasilewska K, Potulska-Chromik A, Szczudlik P, Kaminska A and Ploski R: Exome sequencing reveals mutations in MFN2 and GDAP1 in severe Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 19:242–245. 2014. View Article : Google Scholar : PubMed/NCBI
16	Guo X, Chen KH, Guo Y, Liao H, Tang J and Xiao RP: Mitofusin 2 triggers vascular smooth muscle cell apoptosis via mitochondrial death pathway. Circ Res. 101:1113–1122. 2007. View Article : Google Scholar : PubMed/NCBI
17	Santel A and Fuller MT: Control of mitochondrial morphology by a human mitofusin. J Cell Sci. 114:867–874. 2001.PubMed/NCBI
18	Schon K, Spasic-Boskovic O, Brugger K, Graves TD, Abbs S, Park SM, Ambegaonkar G and Armstrong R: Mosaicism for a pathogenic MFN2 mutation causes minimal clinical features of CMT2A in the parent of a severely affected child. Neurogenetics. 18:49–55. 2017. View Article : Google Scholar : PubMed/NCBI
19	Helbig I, Hodge SE and Ottman R: Familial cosegregation of rare genetic variants with disease in complex disorders. Eur J Hum Genet. 21:444–450. 2013. View Article : Google Scholar : PubMed/NCBI
20	Deng Y, Wang CC, Choy KW, Du Q, Chen J, Wang Q, Li L, Chung TK and Tang T: Therapeutic potentials of gene silencing by RNA interference: Principles, challenges, and new strategies. Gene. 538:217–227. 2014. View Article : Google Scholar : PubMed/NCBI
21	Kanasty R, Dorkin JR, Vegas A and Anderson D: Delivery materials for siRNA therapeutics. Nat Mater. 12:967–977. 2013. View Article : Google Scholar : PubMed/NCBI
22	Nizzardo M, Simone C, Falcone M, Locatelli F, Riboldi G, Comi GP and Corti S: Human motor neuron generation from embryonic stem cells and induced pluripotent stem cells. Cell Mol Life Sci. 67:3837–3847. 2010. View Article : Google Scholar : PubMed/NCBI
23	Ekins S, Litterman NK, Arnold RJ, Burgess RW, Freundlich JS, Gray SJ, Higgins JJ, Langley B, Willis DE, Notterpek L, et al: A brief review of recent Charcot-Marie-Tooth research and priorities. F1000 Res. 4:532015.