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Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease

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Abstract

The autosomal-dominant axonal peripheral neuropathies comprise a genetically heterogeneous group of disorders that are clinically subsumed under Charcot-Marie-Tooth disease type 2 (CMT2). A significant increase in the number of genes underlying major forms of CMT2 has improved the classification of specific CMT phenotypes. The molecular dissection of cellular functions of the related gene products has only begun and detailed pathophysiological models are still missing, but already the biological scope of genes linked to CMT2 is more diversified than CMT1. The known CMT2 genes present key players in these pathways and will likely prove as powerful tools in identifying eventual future targets for therapeutic intervention.

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References

  • Antonellis A., Ellsworth R. E., Sambuughin N., et al. (2003) Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72, 1293–1299.

    PubMed  CAS  Google Scholar 

  • Auer-Grumbach M. (2004) Hereditary sensory neuropathies. Drugs Today (Barc.) 40, 385–394.

    CAS  Google Scholar 

  • Auer-Grumbach M., De Jonghe P., Wagner K., Verhoeven K., Hartung H. P., and Timmerman V. (2000) Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus. Neurology 55, 1552–1557.

    PubMed  CAS  Google Scholar 

  • Auer-Grumbach M., Strasser-Fuchs S., Robl T., Windpassinger C., and Wagner K. (2003) Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene. Neurology 61, 1435–1437.

    PubMed  CAS  Google Scholar 

  • Barhoumi C., Amouri R., Ben Hamida C., et al. (2001) Linkage of a new locus for autosomal recessive axonal form of Charcot Marie-Tooth disease to chromosome 8q21.3. Neuromuscul. Disord. 11, 27–34.

    PubMed  CAS  Google Scholar 

  • Baxter R. V., Ben Othmane K., Rochelle J. M., et al. (2002) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat. Genet. 30, 21–22.

    PubMed  CAS  Google Scholar 

  • Ben Othmane K., Middleton L. T., Loprest L., et al. (1993) Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics 17, 1–6.

    Google Scholar 

  • Ben Othmane K., Lennon F., Loeb D., et al. (1994) Autosomal recessive Charcot-Marie-Tooth disease: classification and genetic linkage of one form (CMT4A) to chromosome 8q. Cold Spring Harbor Laboratory Genome Mapping and Sequencing Meeting, May 11–15, Cold Spring Harbor, NY.

  • Benndorf R., Sun X., Gilmont R. R., et al. (2001) HSP22, a new member of the small heat shock protein superfamily, interacts with mimic of phosphorylated HSP27 ((3D)HSP27). J. Biol. Chem. 276, 26,753–26,761.

    CAS  Google Scholar 

  • Berciano J., Combarros O., Figols J., et al. (1986) Hereditary motor and sensory neuropathy type II. Clinicopathological study of a family. Brain 109, 897–914.

    PubMed  Google Scholar 

  • Boerkoel C. F., Takashima H., Garcia C. A., et al. (2002) charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann. Neurol. 51, 190–201.

    PubMed  CAS  Google Scholar 

  • Bottger G., Nagelkerken B., and van der S. P. (1996) Rab4 and Rab7 define distinct nonoverlapping endosomal compartments. J. Biol. Chem. 271, 29,191–29,197.

    CAS  Google Scholar 

  • Carra S., Sivilotti M., Chavez Zobel A. T., Lambert H., and Landry J. (2005) HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Hum. Mol. Genet. 14, 1659–1669.

    PubMed  CAS  Google Scholar 

  • Chen H. and Chan D. C. (2004) Mitochondrial dynamics in mammals. Curr. Top. Dev. Biol. 59, 119–144.

    PubMed  CAS  Google Scholar 

  • Claramunt R., Pedrola L., Sevilla T., et al. (2005) Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J. Med. Genet. 42, 358–365.

    PubMed  CAS  Google Scholar 

  • Cuesta A., Pedrola L., Sevilla T., et al. (2002) The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat. Genet. 30, 22–25.

    PubMed  CAS  Google Scholar 

  • De Jonghe P., Timmerman V., Ceuterick C., et al. (1999) The Thr124 Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot-Marie-Tooth phenotype. Brain 122, 281–290.

    PubMed  Google Scholar 

  • Dyck P. J., Litchy W. J., Minnerath S., et al. (1994) Hereditary Motor and Sensory Neuropathy with Diaphragm and Vocal Cord Paresis. Ann. Neurol. 35, 608–615.

    PubMed  CAS  Google Scholar 

  • Evgrafov O. V., Mersiyanova I., Irobi J., et al. (2004) Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat. Genet. 36, 602–606.

    PubMed  CAS  Google Scholar 

  • Fabrizi G. M., Cavallaro T., Angiari C., et al. (2004) Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology 62, 1429–1431.

    PubMed  CAS  Google Scholar 

  • Feng Y., Press B., and Wandinger-Ness A. (1995) Rab 7: an important regulator of late endocytic membrane traffic. J. Cell Biol. 131, 1435–1452.

    PubMed  CAS  Google Scholar 

  • Ganea E. (2001) Chaperone-like activity of alpha-crystallin and other small heat shock proteins. Curr. Protein Pept. Sci. 2, 205–225.

    PubMed  CAS  Google Scholar 

  • Georgiou D. M., Zidar J., Korosec M., Middleton L. T., Kyriakides T., and Christodoulou K. (2002) A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family. Neurogenetics 4, 93–96.

    PubMed  CAS  Google Scholar 

  • Harding A. E. and Thomas P. K. (1980a) Genetic aspects of hereditary motor and sensory neuropathy (types I and II). J. Med. Genet. 17, 329–336.

    PubMed  CAS  Google Scholar 

  • Harding A. E. and Thomas P. K. (1980b) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103, 259–280.

    PubMed  CAS  Google Scholar 

  • Houlden H., King R. H., Muddle J. R., et al. (2004) A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann. Neurol. 56, 586–590.

    PubMed  CAS  Google Scholar 

  • Irobi J., Van Impe K., Seeman P., et al. (2004) Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat. Genet. 36, 597–601.

    PubMed  CAS  Google Scholar 

  • Ismailov S. M., Fedotov V. P., Dadali E. L., et al. (2001) A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21. Eur. J. Human Genet. 9, 646–650.

    CAS  Google Scholar 

  • Jordanova A., De Jonghe P., Boerkoel C. F., et al. (2003) Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 126, 590–597.

    PubMed  CAS  Google Scholar 

  • Kappe G., Franck E., Verschuure P., Boelens W. C., Leunissen J. A., and de Jong W. W. (2003) The human genome encodes 10 alpha-crystallin-related small heat shock proteins: HspB1-10. Cell Stress. Chaperomes. 8, 53–61.

    CAS  Google Scholar 

  • Kijima K., Numakura C., Izumino H., et al. (2005) Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum. Genet. 116, 23–27.

    PubMed  CAS  Google Scholar 

  • Klein C. J., Cunningham J. M., Atkinson E. J., et al. (2003) The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders. Neurology 60, 1151–1156.

    PubMed  CAS  Google Scholar 

  • Koshiba T., Detmer S. A., Kaiser J. T., Chen H., McCaffery J. M., and Chan D. C. (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305, 858–862.

    PubMed  CAS  Google Scholar 

  • Lawson V. H., Graham B. V., and Flanigan K. M. (2005) Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 65, 197–204.

    PubMed  CAS  Google Scholar 

  • Marco A., Cuesta A., Pedrola L., Palau F., and Marin I. (2003) Evolutionary and Structural Analyses of GDAP1, Involved in Charcot-Marie-Tooth Disease, Characterize a Novel Class of Glutathione Transferase-Related Genes. Mol. Biol. Evol. 21, 176–187.

    PubMed  Google Scholar 

  • Marrosu M. G., Vaccargiu S., Marrosu G., Vannelli A., Cianchetti C., and Muntoni F. (1998) Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology 50, 1397–1401.

    PubMed  CAS  Google Scholar 

  • Mehlen P., Preville X., Chareyron P., Briolay J., Klemenz R., and Arrigo A. P. (1995) Constitutive expression of human hsp27, Drosophila hsp27, or human alpha B-crystallin confers resistance to TNF- and oxidative stress-induced cytotoxicity in stably transfected murine L929 fibroblasts. J. Immunol. 154, 363–374.

    PubMed  CAS  Google Scholar 

  • Meresse S., Gorvel J. P., and Chavrier P. (1995) The rab7 GTPase resides on a vesicular compartment connected to lysosomes. J. Cell Sci. 108, 3349–3358.

    PubMed  CAS  Google Scholar 

  • Mersiyanova I. V., Perepelov A. V., Polyakov A. V., et al. (2000) A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am. J. Hum. Genet. 67, 37–46.

    PubMed  CAS  Google Scholar 

  • Misu K., Yoshihara T., Shikama Y., et al. (2000) An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val). J. Neurol. Neurosurg. Psychiatry 69, 806–811.

    PubMed  CAS  Google Scholar 

  • Nagamatsu M., Jenkins R.B., Schaid D. J., Klein D. M., and Dyck P. J. (2000) Hereditary motor and sensory neuropathy type 2C is genetically distinct from types 2B and 2D. Arch. Neurol. 57, 669–672.

    PubMed  CAS  Google Scholar 

  • Nelis E., Berciano J., Verpoorten N., et al. (2004) Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2G) maps to chromosome 12q12-q13.3. J. Med. Genet. 41, 193–197.

    PubMed  CAS  Google Scholar 

  • Nelis E., Erdem S., Van Den Bergh P. Y., et al. (2002) Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. Neurology 59, 1865–1872.

    PubMed  CAS  Google Scholar 

  • Nunnari J., Marshall W. F., Straight A., Murray A., Sedat J. W., and Walter P. (1997) Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA. Mol. Biol. Cell 8, 1233–1242.

    PubMed  CAS  Google Scholar 

  • Pedrola L., Espert A., Wu X., Claramunt R., Shy M. E., and Palau F. (2005) GDAP1, the protein causing Charcot-Marie-Tooth disease type4A, is expressed in neurons and is associated with mitochondria. Hum. Mol. Genet. 14, 1087–1094.

    PubMed  CAS  Google Scholar 

  • Perez-Olle R., Lopez-Toledano M. A., Goryunov D., et al. (2005) Mutations in the neurofilament light gene linked to Charcot-Marie-Tooth disease cause defects in transport. J. Neurochem. 93, 861–874.

    PubMed  CAS  Google Scholar 

  • Pich S., Bach D., Briones P., et al. (2005) The Charcot-Marie-Tooth type 2A gene product, Mfn2, upregulates fuel oxidation through expression of OXPHOS system. Hum. Mol. Genet. 14, 1405–1415.

    PubMed  CAS  Google Scholar 

  • Preville X., Salvemini F., Giraud S., et al. (1999) Mammalian small stress proteins protect against oxidative stress through their ability to increase glucose-6-phosphate dehydrogenase activity and by maintaining optimal cellular detoxifying machinery. Exp. Cell Res. 247, 61–78.

    PubMed  CAS  Google Scholar 

  • Rojo M., Legros F., Chateau D., and Lombes A. (2002) Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J. Cell Sci. 115, 1663–1674.

    PubMed  CAS  Google Scholar 

  • Saifi G. M., Szigeti K., Wiszniewski W., et al. (2005) SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum. Mutat. 25, 372–383.

    PubMed  CAS  Google Scholar 

  • Santel A. and Fuller M. T. (2001) Control of mitochondrial morphology by a human mitofusin. J. Cell Sci. 114, 867–874.

    PubMed  CAS  Google Scholar 

  • Seeman P., Mazanec R., Huehne K., SuEslikova P., Keller O., and Rautenstrauss B. (2004) Hearing loss as the first feature of late-onset axonal CMT disease due to a novel P0 mutation. Neurology 63, 733–735.

    PubMed  CAS  Google Scholar 

  • Senderek J., Bergmann C., Ramaekers V. T., et al. (2003) Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain 126, 642–649

    PubMed  Google Scholar 

  • Senderek J., Hermanns B., Hartmann C., and Schröder J. M. (1999) P0 point mutations in Charcot-Marie-Tooth neuropathy type 2: two novel amino acid substitutions (Tyr119Cys; Asp61Gly) and a possible “hot spot” on Thr124. European Charcot-Marie-Tooth Consortium 8th Annual Symposium, Antwerp, Belgium.

  • Shiba K., Schimmel P., Motegi H., and Noda T. (1994) Human glycyl-tRNA synthetase. Wide divergence of primary structure from bacterial counterpart and species-specific aminoacylation. J. Biol. Chem. 269, 30,049–30,055.

    CAS  Google Scholar 

  • Shy M. E., Jani A., Krajewski K., et al. (2004) Phenotypic clustering in MPZ mutations. Brain 127, 371–384.

    PubMed  Google Scholar 

  • Sivakumar K., Kyriakides T., Puls I., et al. (2005) Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain 128, 2304–2314.

    PubMed  Google Scholar 

  • Skre H. (1974) Genetic and clinical aspects of CMT disease. Clin. Genet. 6, 78–118.

    Google Scholar 

  • Sowden J. E., Logigian E. L., Malik K., and Herrmann D. N. (2005) Genotype-phenotype correlation in a family with late onset CMT and an MPZ lys236del mutation. J. Neurol. Neurosurg. Psychiatry 76, 442–444.

    PubMed  CAS  Google Scholar 

  • Tang B. S., Luo W., Xia K., et al. (2004) A new locus for autosomal dominant Charcot-Marie-Tooth disease type2 (CMT2L) maps to chromosome 12q24. Hum Genet 114, 527–533.

    PubMed  CAS  Google Scholar 

  • Tang B. S., Zhao G.H., Luo W., et al. (2005) Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type2L. Hum. Genet. 116, 222–224.

    PubMed  CAS  Google Scholar 

  • Vance J. M. (2000) The many faces of Charcot-Marie-Tooth disease. Arch. Neurol. 57, 638–640.

    PubMed  CAS  Google Scholar 

  • Vance J. M., Speer M. C., Stajich J. M., et al. (1996) Misclassification and linkage of hereditary sensory and autonomic neuropathy type1 as Charcot-Marie-Tooth disease, type 2B. Am. J. Hum. Genet. 59, 258–260.

    PubMed  CAS  Google Scholar 

  • Verhoeven K., De Jonghe P., Coen K., et al. (2003) Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72, 722–727.

    PubMed  CAS  Google Scholar 

  • Zhang F., Tang B., Zhao G., et al. (2005) Mutation analysis of small heat-shock protein 22 gene in Chinese patients with Charcot-Marie-Tooth disease. Zhonghua Yi. Xue. Yi. Chuan Xue. Za Zhi. 22, 361–363.

    PubMed  Google Scholar 

  • Zhao C., Takita J., Tanaka Y., et al. (2001) Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105, 587–597.

    PubMed  CAS  Google Scholar 

  • Zhou L. and Griffin J. W. (2003) Demyelinating neuropathies. Curr. Opin. Neurol. 16, 307–313.

    PubMed  Google Scholar 

  • Zhu D., Kennerson M. L., Walizada G., Zuchner S., Vance J. M., and Nicholson G. A. (2005) CMT with pyramidalsigns is genetically heterogenous: families with and without MFN2 mutations. Neurol 65, 496, 497.

    CAS  Google Scholar 

  • Zuchner S., Mersiyanova I. V., Muglia M., et al. (2004a) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type2A. Nat. Genet. 36, 449–451.

    PubMed  Google Scholar 

  • Zuchner S., Vorgerd M., Sindern E., and Schroder J. M. (2004b) The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. Neuromuscul. Disord. 14, 147–157.

    PubMed  Google Scholar 

  • Zuchner S., Noureddine M., Kennerson M., et al. (2005) Mutations in the pleckstrin homology of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat. Genet. 37, 289–294.

    PubMed  Google Scholar 

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  1. Center for Human Genetics, Duke University Medical Center, 595 LaSalle Street, Box 3445 DUMC, 27710, Durham, NC, USA

    Stephan Züchner & Jeffery M. Vance

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  1. Stephan Züchner
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Correspondence to Stephan Züchner.

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Züchner, S., Vance, J.M. Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease. Neuromol Med 8, 63–74 (2006). https://doi.org/10.1385/NMM:8:1-2:63

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