Domain / Mutation / Number of unrelated cases described in literature / References / Additional informations
N-ter / Lys38del / c.113_115delAGA / 1 / 1 / In compound heterozygosis with MFN2:p.[Thr362Met]1
N-ter / Gln45Arg / c.134A>G / 1 / 2
N-ter / Val69Phe / c.205G>T / 1 / 3
N-ter / Leu76Pro / c.227T>C / 2 / 3,4
N-ter / Leu92Arg / c.275T>G / 1 / 5
N-ter / Leu92Pro / c.275T>C / 2 / 4,6
N-ter / Arg94Trp / c.280C>T / 18 / 4,6-15
N-ter / Arg94Gln / c.281G>A / 13 / 3,4,10,12,14-18
N-ter / Arg94Gly / NR / 3 / 15
N-ter / Arg94Pro / c.281G>C / 1 / this work
N-ter / Lys98Glu / c.292A>G / 1 / 19
GTP-asic / Ala100Gly / c.299C>G / 1 / 4
GTP-asic / Arg104Trp / c.310C>T / 10 / 9,11,19-23
GTP-asic / Thr105Met / c.314C>T / 3 / 6,15,24
GTP-asic / Gly108Arg / c.322G>A / 1 / 9 / In compound heterozygosis with MFN2:p.[Arg707Trp]9
GTP-asic / Pro123Leu / c.368C>T / 2 / 4,18
GTP-asic / Gly127Asp / c.380G>A / 1 / 6
GTP-asic / Gly127Val / c.380G>T / 1 / 25
GTP-asic / His128Arg / c.383A>G / 1 / 9
GTP-asic / Asn131Ser / c.392A>G / 1 / 26 / In homozygosis26
GTP-asic / Leu146Phe / c.436C>T / 1 / 27
GTP-asic / Ser156Ile / c.467G>T / 1 / 9
GTP-asic / - / c.474+4A>G / 1 / 28 / In cis with MFN2:p.[Phe223Tyr]28
GTP-asic / - / c.475-1G>T / 1 / 29
GTP-asic / - / c.475-1G>C
(IVS5-1G>C) / 2 / 11,20
GTP-asic / Val160fsTer26 / c.479_480delTG / 1 / 30 / In heterozygosis associated to GDAP: p.[Arg120Trp]30
GTP-asic / Ala164Val / c.491C>T / 2 / 19,31 / In compound heterozygosis with MFN2:p.[Thr362Met]19,31
GTP-asic / His165Asp / c.493C>G / 1 / 32
GTP-asic / His165Tyr / c.493C>T / 1 / 4
GTP-asic / His165Arg / c.494A>G / 6 / 4,6,8,11, this work
GTP-asic / His165Leu / c.494A>T / 1 / 33 / Associated to amyotrophic lateral sclerosis
GTP-asic / Ser200ArgfsTer61
(del ex 7-8) / - / 1 / 1 / In compound heterozygosis with MFN2:p.[Phe216Ser]1
GTP-asic / Ile203Met / c.609T>G / 1 / 12
GTP-asic / Thr206Ile / c.617C>T / 4 / 4,7
GTP-asic / Asp210Val / c.629A>T / 1 / 34
GTP-asic / Ile213Thr / c.638T>C / 1 / 24
GTP-asic / Asp214Asn / c.640G>A / 2 / 19,31 / In compound heterozygosis with MFN2:p.[Cys390Arg]19,31
GTP-asic / Phe216Ser / c.647T>C / 2 / 1,19 / in homozygosis19 or compound heterozygosis1 with MFN2:p.[Ser200ArgfsX61]
GTP-asic / Phe223Leu / c.669T>A / 1 / 35
GTP-asic / Phe223Tyr / c.668T>A / 1 / 28 / In cis with MFN2:c.[474+4A>G]28
GTP-asic / Val226_Ser229del / c.677_688del12 / 1 / 36
GTP-asic / Thr232Ala / c.694A>G / 1 / 18
GTP-asic / Thr236Met / c.707C>T / 2 / 9,35
GTP-asic / Phe240Ile / c.718T>A / 1 / 37
GTP-asic / Val244Met / c.730G>A / 2 / 9,35
GTP-asic / Leu248Val / c.742C>G / 1 / 15
GTP-asic / Arg250Trp / c.748C>T / 1 / 4 / In compound heterozygosis with MFN2:p.[Arg400X]4
GTP-asic / Arg250Gln / c.749G>A / 2 / 4,5
GTP-asic / Pro251Ala / c.751C>G / 1 / 3
GTP-asic / Pro251Arg / c.752C>G / 2 / 5,15
GTP-asic / Asn252Lys / c.756C>A / 1 / 12
GTP-asic / Arg259Leu / c.776G>T / 1 / 38
interdomain / Ser263Pro / c.787T>C / 2 / 6,8
interdomain / Val273Gly / c.818T>G / 1 / 24
interdomain / Gln276Arg / c.827A>G / 3 / 4,7,9
interdomain / Gln276His / c.828G>C / 2 / 12,39
interdomain / His277Tyr / c.829C>T / 1 / 9
interdomain / His277Arg / c.830A>G / 1 / 4
interdomain / Arg280His / c.839G>A / 7 / 3,4,6,11,40,41
interdomain / Phe284Tyr / c.851T>A / 1 / 35
interdomain / Glu288Asp / c.864G>C / 1 / 42
interdomain / Gly298Arg / c.892G>A / 1 / 12
interdomain / Glu308Ter / c.922G>T / 1 / 1 / In compound heterozygosis with MFN2:p.[ Arg519Pro]1
interdomain / Glu329del / c.984_986delAGA / 1 / this work
interdomain / Glu347Val / c.1040A>T / 1 / 25
interdomain / Ser350Pro / c.1048T>C / 2 / 8,11
interdomain / Thr356Ala / c.1066 A>G / 1 / 43
interdomain / Lys357Asn / c.1071G>C / 1 / 35
interdomain / His361Tyr / c.1081C>T / 3 / 4,7,15
interdomain / Thr362Met / c.1085C>T / 4 / 1,6,19,31 / In compound heterozygosis with MFN2:p.[Ala164Val]19,31 or p.[Lys38del]1
interdomain / Arg364Trp / c.1090C>T / 19 / 6,7,11,13,15,29,44,45 , this work
interdomain / Arg364Pro / c.1091G>C / 4 / 9,15,46
interdomain / Arg364Gln / c.1091G>A / 3 / 9,12,17
interdomain / Met 376Val / c.1126A>G / 2 / 12,36
interdomain / Met376Leu / c.1126A>C / 1 / 5
interdomain / Met376Thr / c.1127T>C / 1 / 6
interdomain / Met376Ile / c.1128G>A / 2 / 4,25
interdomain / Ser378Pro / c.1132T>C / 1 / 20
interdomain / Leu379_Met381del / c.1134_1142delCCTGCACAT / 1 / 4
interdomain / Ala383Val / c.1148C>T / 1 / 47
interdomain / Gln386Pro / c.[1157A>C;1158G>T] / 1 / 4
interdomain / Cys390Arg / c.1168T >C / 2 / 19,31 / In compound heterozygosis with MFN2:p.[Asp214Asn]19,31
interdomain / Cys390Phe / c.1169G>T / 1 / 15
interdomain / Arg400Ter / c.1198C>T / 1 / 4 / In compound heterozygosis with MFN2:p.[Arg250Trp]4
interdomain / Arg400Pro / c.1199G>C / 1 / 22
HR1 / Arg418Ter / c.1252C>T / 2 / 7,11
HR1 / Glu424Gly / c.1271A>G / 1 / 35
interdomain 2 / Pro456Leu / c.1367C>T / 1 / 48 / Associated with early-onset stroke48
interdomain 2 / - / c.1392+2T>C / 1 / 49
interdomain 2 / Arg468His / c.1403G>A / 11 / 5,10,12,14,25,50 / In compound heterozygosis with GDAP:p.[Gln163Ter]50
interdomain 2 / Arg519Pro / c.1556G>C / 1 / 1 / In compound heterozygosis with MFN2:p.[Glu308Ter]1
interdomain 2 / Asn570Ser / c.1709A>G / 2 / 10,14 / Associated with dHMN14
interdomain 2 / Phe665Ser / c.1994T>C / 1 / 9
C-ter / Val705Ile / c.2219G>C / 7 / 5,10,14,25,40 / Demonstrated as polymorphism51
C-ter / Thr706Pro / c.2116A>C / 1 / this work
C-ter / Arg707Trp / c.2119C>T / 4 / 9,10,14,31 / In homozygosis31 or compound heterozygosis9 with MFN2:p.[Gly108Arg]
C-ter / Arg707_Asn709del / c.2120delGGGAGAACC / 1 / 5
C-ter / Arg707Pro / c.2120G>C / 1 / 36
C-ter / Leu710Pro / c.2129T>C / 1 / 4
C-ter / Ile714Val / c.2140A>G / 1 / 40
C-ter / Ala716Thr / c.2146G>A / 3 / 10,15 / associated with intermediate CMT10
C-ter / Leu734Val / c.2200C>G / 1 / 37
C-ter / Ala738Val / c.2213C>T / 3 / 40,52, this work
C-ter / Trp740Ser / c.2219G>C / 4 / 3,4,15
C-ter / Trp740Arg / c.2218T>C / 1 / 13
C-ter / Trp740Cys / c.2220G>C / 1 / 9
C-ter / Glu744Met / c.2230_2231delinsAT / 1 / 29
C-ter / Leu745Pro / c.2234T>C / 1 / 9
C-ter / Met747Thr / c.2240T>C / 1 / 9
C-ter / His750Pro / c.2249A>C / 1 / 15
C-ter / Gln751Ter / c.2251C>T / 2 / 4
C-ter / Tyr752Ter / c.2256C>A / 1 / 15
C-ter / Leu753fs9 / c.2258_2259insT / 1 / 25

Tab. S1: List of MFN2 mutations described in the literature with the number of independent patients reported and all the references. The up to date guidelines of HGVS (http://www.hgvs.org/) where used for nomenclature. When different, the mutation reported in the literature with an old nomenclature is shown in brackets for sake of clarity.

1. Polke JM, Laura M, Pareyson D et al: Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations. Neurology 2011; 77: 168-173.

2. Bienfait HM, Baas F, Koelman JH et al: Phenotype of Charcot-Marie-Tooth disease Type 2. Neurology 2007; 68: 1658-1667.

3. Zuchner S, Mersiyanova IV, Muglia M et al: Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nature genetics 2004; 36: 449-451.

4. Verhoeven K, Claeys KG, Zuchner S et al: MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain : a journal of neurology 2006; 129: 2093-2102.

5. McCorquodale DS, 3rd, Montenegro G, Peguero A et al: Mutation screening of mitofusin 2 in Charcot-Marie-Tooth disease type 2. Journal of neurology 2011; 258: 1234-1239.

6. Chung KW, Kim SB, Park KD et al: Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain : a journal of neurology 2006; 129: 2103-2118.

7. Zuchner S, De Jonghe P, Jordanova A et al: Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Annals of neurology 2006; 59: 276-281.

8. Cho HJ, Sung DH, Kim BJ, Ki CS: Mitochondrial GTPase mitofusin 2 mutations in Korean patients with Charcot-Marie-Tooth neuropathy type 2. Clinical Genetics 2007; 71: 267-272.

9. Calvo J, Funalot B, Ouvrier RA et al: Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations. Archives of neurology 2009; 66: 1511-1516.

10. Braathen GJ, Sand JC, Lobato A, Hoyer H, Russell MB: MFN2 point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families. BMC medical genetics 2010; 11: 48.

11. Chung KW, Suh BC, Cho SY et al: Early-onset Charcot-Marie-Tooth patients with mitofusin 2 mutations and brain involvement. Journal of neurology, neurosurgery, and psychiatry 2010; 81: 1203-1206.

12. Casasnovas C, Banchs I, Cassereau J et al: Phenotypic spectrum of MFN2 mutations in the Spanish population. Journal of medical genetics 2010; 47: 249-256.

13. Lv H, Wang L, Li W et al: Mitofusin 2 gene mutation causing early-onset CMT2A with different progressive courses. Clinical neuropathology 2013; 32: 16-23.

14. Braathen GJ: Genetic epidemiology of Charcot-Marie-Tooth disease. Acta neurologica Scandinavica Supplementum 2012: iv-22.

15. Feely SM, Laura M, Siskind CE et al: MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology 2011; 76: 1690-1696.

16. Neusch C, Senderek J, Eggermann T, Elolff E, Bahr M, Schneider-Gold C: Mitofusin 2 gene mutation (R94Q) causing severe early-onset axonal polyneuropathy (CMT2A). European journal of neurology : the official journal of the European Federation of Neurological Societies 2007; 14: 575-577.

17. Banchs I, Casasnovas C, Montero J, Martinez-Matos JA, Volpini V: Two Spanish families with Charcot-Marie-Tooth type 2A: clinical, electrophysiological and molecular findings. Neuromuscular disorders : NMD 2008; 18: 974-978.

18. Sole G, Ferrer X, Vital C, Martin-Negrier ML, Vital A, Latour P: Ultrastructural mitochondrial modifications characteristic of mitofusin 2 mutations (CMT2A). Journal of the peripheral nervous system : JPNS 2009; 14: 206-207.

19. Vallat JM, Ouvrier RA, Pollard JD et al: Histopathological findings in hereditary motor and sensory neuropathy of axonal type with onset in early childhood associated with mitofusin 2 mutations. Journal of neuropathology and experimental neurology 2008; 67: 1097-1102.

20. Brockmann K, Dreha-Kulaczewski S, Dechent P et al: Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations. Journal of neurology 2008; 255: 1049-1058.

21. Del Bo R, Moggio M, Rango M et al: Mutated mitofusin 2 presents with intrafamilial variability and brain mitochondrial dysfunction. Neurology 2008; 71: 1959-1966.

22. Baets J, Deconinck T, De Vriendt E et al: Genetic spectrum of hereditary neuropathies with onset in the first year of life. Brain : a journal of neurology 2011; 134: 2664-2676.

23. Genari AB, Borghetti VH, Gouvea SP et al: Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot-Marie-Tooth type 2. Neuromuscular disorders : NMD 2011; 21: 428-432.

24. Lawson VH, Graham BV, Flanigan KM: Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 2005; 65: 197-204.

25. Engelfried K, Vorgerd M, Hagedorn M et al: Charcot-Marie-Tooth neuropathy type 2A: novel mutations in the mitofusin 2 gene (MFN2). BMC medical genetics 2006; 7: 53.

26. Fischer C, Trajanoski S, Papić L et al: SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease. Journal of neurology 2012; 259: 515-523.

27. Klein CJ, Kimmel GW, Pittock SJ et al: Large kindred evaluation of mitofusin 2 novel mutation, extremes of neurologic presentations, and preserved nerve mitochondria. Archives of neurology 2011; 68: 1295-1302.

28. Park SY, Kim SY, Hong YH, Cho SI, Seong MW, Park SS: A novel double mutation in cis in MFN2 causes Charcot-Marie-Tooth neuropathy type 2A. Neurogenetics 2012; 13: 275-280.

29. Lin KP, Soong BW, Yang CC et al: The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan. PloS one 2011; 6: e29393.

30. Vital A, Latour P, Sole G et al: A French family with Charcot-Marie-Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations. Neuromuscular disorders : NMD 2012; 22: 735-741.

31. Nicholson GA, Magdelaine C, Zhu D et al: Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations. Neurology 2008; 70: 1678-1681.

32. Zhu D, Kennerson ML, Walizada G, Züchner S, Vance JM, Nicholson GA: Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology 2005; 65: 496-497.

33. Marchesi C, Ciano C, Salsano E et al: Co-occurrence of amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease type 2A in a patient with a novel mutation in the mitofusin-2 gene. Neuromuscular disorders : NMD 2011; 21: 129-131.

34. Rouzier C, Bannwarth S, Chaussenot A et al: The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype. Brain : a journal of neurology 2012; 135: 23-34.

35. Kijima K, Numakura C, Izumino H et al: Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Human genetics 2005; 116: 23-27.