#601098
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 1C (CMT1C) is caused by heterozygous mutation in the LITAF gene (603795) on chromosome 16p13.
For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).
Chance et al. (1992) reported 2 unrelated kindreds (K1550 and K1551) with autosomal dominant demyelinating CMT affecting multiple generations. All affected individuals had distal muscle weakness and atrophy and depressed deep tendon reflexes. Variable pes cavus and sensory loss were also present. Mean median motor nerve conduction velocities were 15 and 22.9 m/s, respectively, in the 2 families. The families had previously been part of a linkage study by Chance et al. (1990), who excluded linkage to chromosome 1 or 17 where CMT1B and CMT1A (118220) had been mapped, respectively. Chance et al. (1992) confirmed the lack of linkage of these 2 families to chromosomes 1q and 17p11.2, indicating the presence of a third locus for CMT1.
Street et al. (2002) restudied the 2 families reported by Chance et al. (1992), which were of Irish and English descent, respectively. Sural nerve biopsy of 1 patient showed onion bulb hypertrophy, consistent with demyelinating Charcot-Marie-Tooth disease.
The transmission pattern of CMT1C in the families reported by Chance et al. (1990, 1992) and Street et al. (2002) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis of 2 families (K1550 and K1551) with CMT1 reported by Chance et al. (1990, 1992), Street et al. (2002) found linkage to chromosome 16p13.1-p12.3. A maximum combined lod score of 14.25 was obtained with marker D16S500. The combined haplotype analysis in the 2 families localized the locus, designated CMT1C, within a 9-cM interval flanked by markers D16S519 and D16S764. The disease-linked haplotypes in the 2 pedigrees were not conserved, suggesting that the gene mutation underlying the disease in each family arose independently. Genetic analysis excluded mutations in the epithelial membrane protein-2 gene (EMP2; 602334), which maps to 16p13.2, with inconclusive results.
Using a combination of standard positional cloning and candidate gene approaches, Street et al. (2003) identified LITAF as the causal gene for CMT1C. They identified 3 missense mutations in this gene (603795.0001-603795.0003), each in a different CMT1C pedigree. Two of the families had previously been reported by Chance et al. (1990, 1992) and Street et al. (2002).
Gerding et al. (2009) identified a heterozygous mutation in the LITAF gene (V144M; 603795.0005) in a German mother and son with CMT1C. Both had typical demyelinating sensorimotor neuropathy, but the son showed initial symptom onset at age 10, whereas the mother had onset of clinical symptoms in her late fifties.
Lee et al. (2011) found that CMT1C-associated LITAF mutations clustered within or around the transmembrane domain and caused mislocalization of the protein from the early endosomal membrane to the cytosol. Mutant proteins were less stable and more prone to aggregation compared to the wildtype protein. Aggregated proteins were degraded by both the proteasome and aggresome-autophagy pathways.
Lee et al. (2013) found that transgenic mice carrying a homozygous Litaf mutation (W116G; 603795.0003) developed progressive motor and sensory impairment associated with decreased motor and sensory nerve conduction velocities similar to that observed in CMT1C. Peripheral nerves of mutant mice showed dysmyelination with reduced axon caliber and focal myelin infoldings near the paranodal and internodal regions. Myelin infolding was often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. The W116G mutant protein was partially mislocalized to the cytosol from the membrane. The findings suggested that the W116G Litaf mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. Myelin infolding and paranodal damage appeared to represent pathogenic precursors preceding demyelination and axonal degeneration in this disorder.
Chance, P. F., Bird, T. D., O'Connell, P., Lipe, H., Lalouel, J.-M., Leppert, M. Genetic linkage and heterogeneity in type I Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy type I). Am. J. Hum. Genet. 47: 915-925, 1990. [PubMed: 2239969, related citations]
Chance, P. F., Matsunami, N., Lensch, W., Smith, B., Bird, T. D. Analysis of the DNA duplication 17p11.2 in Charcot-Marie-Tooth neuropathy type 1 pedigrees: additional evidence for a third autosomal CMT1 locus. Neurology 42: 2037-2041, 1992. [PubMed: 1407588, related citations] [Full Text]
Gerding, W. M., Koetting, J., Epplen, J. T., Neusch, C. Hereditary and sensory neuropathy caused by a novel mutation in LITAF. Neuromusc. Disord. 19: 701-703, 2009. [PubMed: 19541485, related citations] [Full Text]
Lee, S. M., Olzmann, J. A., Chin, L.-S., Li, L. Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways. J. Cell Sci. 124: 3319-3331, 2011. [PubMed: 21896645, images, related citations] [Full Text]
Lee, S. M., Sha, D., Mohammed, A. A., Asress, S., Glass, J. D., Chin, L.-S., Li, L. Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot-Marie-Tooth disease type 1C. Hum. Molec. Genet. 22: 1755-1770, 2013. [PubMed: 23359569, images, related citations] [Full Text]
Street, V. A., Bennett, C. L., Goldy, J. D., Shirk, A. J., Kleopa, K. A., Tempel, B. L., Lipe, H. P., Scherer, S. S., Bird, T. D., Chance, P. F. Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology 60: 22-26, 2003. [PubMed: 12525712, related citations] [Full Text]
Street, V. A., Goldy, J. D., Golden, A. S., Tempel, B. L., Bird, T. D., Chance, P. F. Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies. Am. J. Hum. Genet. 70: 244-250, 2002. [PubMed: 11713717, images, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 4183003; ORPHA: 101083; DO: 0110151;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.13 | Charcot-Marie-Tooth disease, type 1C | 601098 | Autosomal dominant | 3 | LITAF | 603795 |
A number sign (#) is used with this entry because Charcot-Marie-Tooth disease type 1C (CMT1C) is caused by heterozygous mutation in the LITAF gene (603795) on chromosome 16p13.
For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).
Chance et al. (1992) reported 2 unrelated kindreds (K1550 and K1551) with autosomal dominant demyelinating CMT affecting multiple generations. All affected individuals had distal muscle weakness and atrophy and depressed deep tendon reflexes. Variable pes cavus and sensory loss were also present. Mean median motor nerve conduction velocities were 15 and 22.9 m/s, respectively, in the 2 families. The families had previously been part of a linkage study by Chance et al. (1990), who excluded linkage to chromosome 1 or 17 where CMT1B and CMT1A (118220) had been mapped, respectively. Chance et al. (1992) confirmed the lack of linkage of these 2 families to chromosomes 1q and 17p11.2, indicating the presence of a third locus for CMT1.
Street et al. (2002) restudied the 2 families reported by Chance et al. (1992), which were of Irish and English descent, respectively. Sural nerve biopsy of 1 patient showed onion bulb hypertrophy, consistent with demyelinating Charcot-Marie-Tooth disease.
The transmission pattern of CMT1C in the families reported by Chance et al. (1990, 1992) and Street et al. (2002) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis of 2 families (K1550 and K1551) with CMT1 reported by Chance et al. (1990, 1992), Street et al. (2002) found linkage to chromosome 16p13.1-p12.3. A maximum combined lod score of 14.25 was obtained with marker D16S500. The combined haplotype analysis in the 2 families localized the locus, designated CMT1C, within a 9-cM interval flanked by markers D16S519 and D16S764. The disease-linked haplotypes in the 2 pedigrees were not conserved, suggesting that the gene mutation underlying the disease in each family arose independently. Genetic analysis excluded mutations in the epithelial membrane protein-2 gene (EMP2; 602334), which maps to 16p13.2, with inconclusive results.
Using a combination of standard positional cloning and candidate gene approaches, Street et al. (2003) identified LITAF as the causal gene for CMT1C. They identified 3 missense mutations in this gene (603795.0001-603795.0003), each in a different CMT1C pedigree. Two of the families had previously been reported by Chance et al. (1990, 1992) and Street et al. (2002).
Gerding et al. (2009) identified a heterozygous mutation in the LITAF gene (V144M; 603795.0005) in a German mother and son with CMT1C. Both had typical demyelinating sensorimotor neuropathy, but the son showed initial symptom onset at age 10, whereas the mother had onset of clinical symptoms in her late fifties.
Lee et al. (2011) found that CMT1C-associated LITAF mutations clustered within or around the transmembrane domain and caused mislocalization of the protein from the early endosomal membrane to the cytosol. Mutant proteins were less stable and more prone to aggregation compared to the wildtype protein. Aggregated proteins were degraded by both the proteasome and aggresome-autophagy pathways.
Lee et al. (2013) found that transgenic mice carrying a homozygous Litaf mutation (W116G; 603795.0003) developed progressive motor and sensory impairment associated with decreased motor and sensory nerve conduction velocities similar to that observed in CMT1C. Peripheral nerves of mutant mice showed dysmyelination with reduced axon caliber and focal myelin infoldings near the paranodal and internodal regions. Myelin infolding was often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. The W116G mutant protein was partially mislocalized to the cytosol from the membrane. The findings suggested that the W116G Litaf mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. Myelin infolding and paranodal damage appeared to represent pathogenic precursors preceding demyelination and axonal degeneration in this disorder.
Chance, P. F., Bird, T. D., O'Connell, P., Lipe, H., Lalouel, J.-M., Leppert, M. Genetic linkage and heterogeneity in type I Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy type I). Am. J. Hum. Genet. 47: 915-925, 1990. [PubMed: 2239969]
Chance, P. F., Matsunami, N., Lensch, W., Smith, B., Bird, T. D. Analysis of the DNA duplication 17p11.2 in Charcot-Marie-Tooth neuropathy type 1 pedigrees: additional evidence for a third autosomal CMT1 locus. Neurology 42: 2037-2041, 1992. [PubMed: 1407588] [Full Text: https://doi.org/10.1212/wnl.42.10.2037]
Gerding, W. M., Koetting, J., Epplen, J. T., Neusch, C. Hereditary and sensory neuropathy caused by a novel mutation in LITAF. Neuromusc. Disord. 19: 701-703, 2009. [PubMed: 19541485] [Full Text: https://doi.org/10.1016/j.nmd.2009.05.006]
Lee, S. M., Olzmann, J. A., Chin, L.-S., Li, L. Mutations associated with Charcot-Marie-Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome-autophagy pathways. J. Cell Sci. 124: 3319-3331, 2011. [PubMed: 21896645] [Full Text: https://doi.org/10.1242/jcs.087114]
Lee, S. M., Sha, D., Mohammed, A. A., Asress, S., Glass, J. D., Chin, L.-S., Li, L. Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot-Marie-Tooth disease type 1C. Hum. Molec. Genet. 22: 1755-1770, 2013. [PubMed: 23359569] [Full Text: https://doi.org/10.1093/hmg/ddt022]
Street, V. A., Bennett, C. L., Goldy, J. D., Shirk, A. J., Kleopa, K. A., Tempel, B. L., Lipe, H. P., Scherer, S. S., Bird, T. D., Chance, P. F. Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology 60: 22-26, 2003. [PubMed: 12525712] [Full Text: https://doi.org/10.1212/wnl.60.1.22]
Street, V. A., Goldy, J. D., Golden, A. S., Tempel, B. L., Bird, T. D., Chance, P. F. Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies. Am. J. Hum. Genet. 70: 244-250, 2002. [PubMed: 11713717] [Full Text: https://doi.org/10.1086/337943]
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