Abstract
Charcot-Marie-Tooth (CMT) disease is among the most common inherited neurological disorders. Mutations in the gene mitofusin 2 (MFN2) cause the axonal subtype CMT2A, which has also been shown to be associated with optic atrophy, clinical signs of first motor neuron involvement, and early onset stroke. Mutations in MFN2 account for up to 20–30% of all axonal CMT type 2 cases. To further investigate the prevalence of MFN2 mutations and to add to the genotypic spectrum, we sequenced all exons of MFN2 in a cohort of 39 CMT2 patients. We identified seven variants, four of which are novel. One previously described change was co-inherited with a PMP22 duplication, which itself causes the demyelinating form CMT1A. Another mutation was a novel in frame deletion, which is a rare occurrence in the genotypic spectrum of MFN2 characterized mainly by missense mutations. Our results confirm a MFN2 mutation rate of ~15–20% in CMT2.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Braathen GJ, Sand JC, Lobato A, Hoyer H and Russell MB (2010) Genetic epidemiology of Charcot-Marie-Tooth in the general population. Eur J Neurol 18(1):39–48
Braathen GJ, Sand JC, Lobato A, Hoyer H, Russell MB (2010) MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families. BMC Med Genet 11:48
Calvo J, Funalot B, Ouvrier RA, Lazaro L, Toutain A, De Mas P, Bouche P, Gilbert-Dussardier B, Arne-Bes MC, Carriere JP, Journel H, Minot-Myhie MC, Guillou C, Ghorab K, Magy L, Sturtz F, Vallat JM, Magdelaine C (2009) Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations. Arch Neurol 66:1511–1516
Casasnovas C, Banchs I, Cassereau J, Gueguen N, Chevrollier A, Martinez-Matos JA, Bonneau D, Volpini V (2010) Phenotypic spectrum of MFN2 mutations in the Spanish population. J Med Genet 47:249–256
Chung KW, Cho SY, Hwang SJ, Kim KH, Yoo JH, Kwon O, Kim SM, Sunwoo IN, Zuchner S, Choi BO (2008) Early-onset stroke associated with a mutation in mitofusin 2. Neurology 70:2010–2011
Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, Suh JS, Hwang JH, Kim WK, Seo BC, Kim SH, Son IH, Kim SM, Sunwoo IN, Choi BO (2006) Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 129:2103–2118
Dyck PJ, Lambert EH (1968) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. Arch Neurol 18:603–618
Engelfried K, Vorgerd M, Hagedorn M, Haas G, Gilles J, Epplen JT, Meins M (2006) Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). BMC Med Genet 7:53
Hodapp JA, Carter GT, Lipe HP, Michelson SJ, Kraft GH, Bird TD (2006) Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes. Arch Neurol 63:112–117
Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, Hayasaka K (2005) Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 116:23–27
Lawson VH, Graham BV, Flanigan KM (2005) Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 65:197–204
Neusch C, Senderek J, Eggermann T, Elolff E, Bahr M, Schneider-Gold C (2007) Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A). Eur J Neurol 14:575–577
Skre H (1974) Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet 6:98–118
Verhoeven K, Claeys KG, Zuchner S, Schroder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R, Saifi GM, Szigeti K, Mancias P, Butler IJ, Kochanski A, Ryniewicz B, De Bleecker J, Van den Bergh P, Verellen C, Van Coster R, Goemans N, Auer-Grumbach M, Robberecht W, Milic Rasic V, Nevo Y, Tournev I, Guergueltcheva V, Roelens F, Vieregge P, Vinci P, Moreno MT, Christen HJ, Shy ME, Lupski JR, Vance JM, De Jonghe P, Timmerman V (2006) MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 129:2093–2102
Wise CA, Garcia CA, Davis SN, Heju Z, Pentao L, Patel PI, Lupski JR (1993) Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMTIA duplication. Am J Hum Genet 53:853–863
Zhu D, Kennerson ML, Walizada G, Zuchner S, Vance JM, Nicholson GA (2005) Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology 65:496–497
Zuchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, Hamilton SR, Van Stavern G, Krajewski KM, Stajich J, Tournev I, Verhoeven K, Langerhorst CT, de Visser M, Baas F, Bird T, Timmerman V, Shy M, Vance JM (2006) Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 59:276–281
Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schroder JM, Vance JM (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–451
Zuchner S, Vance JM (2006) Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease. Neuromolecular Med 8:63–74
Acknowledgments
The participation of the patients and families in this study is gratefully acknowledged. The study was supported by grants by the Charcot-Marie-Tooth Association (to S.Z.) and the National Institute of Neurological Disorders and Stroke (to S.Z., R01NS052767).
Conflict of interest
Drs. Vance and Züchner are part of a license agreement with Athena Diagnostics Inc.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
McCorquodale, D.S., Montenegro, G., Peguero, A. et al. Mutation screening of mitofusin 2 in Charcot-Marie-Tooth disease type 2. J Neurol 258, 1234–1239 (2011). https://doi.org/10.1007/s00415-011-5910-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-011-5910-7