#601382
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 4B1 (CMT4B1) is caused by homozygous mutation in the MTMR2 gene (603557), which encodes myotubularin-related protein-2, on chromosome 11q21.
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Quattrone et al. (1996) and Bolino et al. (1996) reported a large consanguineous southern Italian family in which 10 members were affected with a distinct form of autosomal recessive demyelinating neuropathy, which they designated Charcot-Marie-Tooth disease type 4B. This motor and sensory neuropathy was characterized pathologically by the presence of focally folded myelin sheaths.
See 256855 and CMT4B2 (604563) for disorders with a similar phenotype.
After exclusion of linkage of CMT4B to loci responsible for other forms of hereditary motor and sensory neuropathy (e.g., 118220, 118200, 118210, and 214400), Bolino et al. (1996) optimized their genomewide search by using homozygosity mapping and haplotype-sharing analysis. Results of this analysis placed the disease locus in the 4-cM interval on chromosome 11q23 delimited by the markers D11S1332 and D11S917.
Using additional physically ordered microsatellite markers from the 11q22 region on the original inbred family, Bolino et al. (2000) narrowed the critical interval for the gene to 2 Mb. After computer analysis of the 33 ESTs assigned to this 2-Mb interval, they demonstrated that 21 different transcripts, as well as 3 known genes, represent potential candidates for the disease.
In unrelated patients with CMT4B1, Bolino et al. (2000) identified 5 different homozygous mutations in the MTMR2 gene (603557.0001-603557.0005). The mutations were either nonsense or frameshifts, most likely leading to lack of functional MTMR2 protein as the cause of the disorder. Bolino et al. (2000) postulated that lack of MTMR2 protein may result in constitutive phosphorylation of an unknown substrate, leading to Schwann cell proliferation with overgrowth of myelin observed in the peripheral nerve.
Exclusion Studies
Bolino et al. (1998) excluded the SCN2B gene (601327) as a candidate for the disorder.
Bonneick et al. (2005) generated a mouse model of CMT4B1 by introducing an E276X mutation in exon 9 of the Mtmr2 gene and deleting the chromosomal region immediately downstream of the stop codon up to within exon 13. The resulting allele closely mimicked the mutation (603557.0002) found in a Saudi Arabian CMT4B1 patient. Animals homozygous for the mutation showed various degrees of complex myelin infoldings and outfoldings exclusively in peripheral nerves. This pathology was progressive with age, and axonal damage was occasionally observed. Distal nerve regions were more affected than proximal parts; however, there were no significant electrophysiologic changes, even in aged (16-month-old) mice, suggesting that myelin infoldings and outfoldings per se may not be invariably associated with detectable electrophysiologic abnormalities.
Bolino, A., Brancolini, V., Bono, F., Bruni, A., Gambardella, A., Romeo, G., Quattrone, A., Devoto, M. Localization of a gene responsible for autosomal recessive demyelinating neuropathy with focally folded myelin sheaths to chromosome 11q23 by homozygosity mapping and haplotype sharing. Hum. Molec. Genet. 5: 1051-1054, 1996. [PubMed: 8817346, related citations] [Full Text]
Bolino, A., Levy, E. R., Muglia, M., Conforti, F. L., LeGuern, E., Salih, M. A. M., Georgiou, D.-M., Christodoulou, R. K., Hausmanowa-Petrusewicz, I., Mandich, P., Gambardella, A., Quattrone, A., Devoto, M., Monaco, A. P. Genetic refinement and physical mapping of the CMT4B gene on chromosome 11q22. Genomics 63: 271-278, 2000. [PubMed: 10673338, related citations] [Full Text]
Bolino, A., Muglia, M., Conforti, F. L., LeGuern, E., Salih, M. A. M., Georgiou, D.-M., Christodoulou, K., Hausmanowa-Petrusewicz, I., Mandich, P., Schenone, A., Gambardella, A., Bono, F., Quattrone, A., Devoto, M., Monaco, A. P. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nature Genet. 25: 17-19, 2000. [PubMed: 10802647, related citations] [Full Text]
Bolino, A., Seri, M., Caroli, F., Eubanks, J., Srinivasan, J., Mandich, P., Schenone, A., Quattrone, A., Romeo, G., Catterall, W. A., Devoto, M. Exclusion of the SCN2B gene as candidate for CMT4B. Europ. J. Hum. Genet. 6: 629-634, 1998. [PubMed: 9887383, related citations] [Full Text]
Bonneick, S., Boentert, M., Berger, P., Atanasoski, S., Mantei, N., Wessig, C., Toyka, K. V., Young, P., Suter, U. An animal model for Charcot-Marie-Tooth disease type 4B1. Hum. Molec. Genet. 14: 3685-3695, 2005. [PubMed: 16249189, related citations] [Full Text]
Quattrone, A., Gambardella, A., Bono, F., Aguglia, U., Bolino, A., Bruni, A. C., Montesi, M. P, Oliveri, R. L., Sabatelli, M., Tamburrini, O., Valentino, P., Van Broeckhoven, C., Zappia, M. Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. Neurology 46: 1318-1324, 1996. [PubMed: 8628474, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 715803003; ORPHA: 99955; DO: 0110191;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q21 | Charcot-Marie-Tooth disease, type 4B1 | 601382 | Autosomal recessive | 3 | MTMR2 | 603557 |
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 4B1 (CMT4B1) is caused by homozygous mutation in the MTMR2 gene (603557), which encodes myotubularin-related protein-2, on chromosome 11q21.
For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Quattrone et al. (1996) and Bolino et al. (1996) reported a large consanguineous southern Italian family in which 10 members were affected with a distinct form of autosomal recessive demyelinating neuropathy, which they designated Charcot-Marie-Tooth disease type 4B. This motor and sensory neuropathy was characterized pathologically by the presence of focally folded myelin sheaths.
See 256855 and CMT4B2 (604563) for disorders with a similar phenotype.
After exclusion of linkage of CMT4B to loci responsible for other forms of hereditary motor and sensory neuropathy (e.g., 118220, 118200, 118210, and 214400), Bolino et al. (1996) optimized their genomewide search by using homozygosity mapping and haplotype-sharing analysis. Results of this analysis placed the disease locus in the 4-cM interval on chromosome 11q23 delimited by the markers D11S1332 and D11S917.
Using additional physically ordered microsatellite markers from the 11q22 region on the original inbred family, Bolino et al. (2000) narrowed the critical interval for the gene to 2 Mb. After computer analysis of the 33 ESTs assigned to this 2-Mb interval, they demonstrated that 21 different transcripts, as well as 3 known genes, represent potential candidates for the disease.
In unrelated patients with CMT4B1, Bolino et al. (2000) identified 5 different homozygous mutations in the MTMR2 gene (603557.0001-603557.0005). The mutations were either nonsense or frameshifts, most likely leading to lack of functional MTMR2 protein as the cause of the disorder. Bolino et al. (2000) postulated that lack of MTMR2 protein may result in constitutive phosphorylation of an unknown substrate, leading to Schwann cell proliferation with overgrowth of myelin observed in the peripheral nerve.
Exclusion Studies
Bolino et al. (1998) excluded the SCN2B gene (601327) as a candidate for the disorder.
Bonneick et al. (2005) generated a mouse model of CMT4B1 by introducing an E276X mutation in exon 9 of the Mtmr2 gene and deleting the chromosomal region immediately downstream of the stop codon up to within exon 13. The resulting allele closely mimicked the mutation (603557.0002) found in a Saudi Arabian CMT4B1 patient. Animals homozygous for the mutation showed various degrees of complex myelin infoldings and outfoldings exclusively in peripheral nerves. This pathology was progressive with age, and axonal damage was occasionally observed. Distal nerve regions were more affected than proximal parts; however, there were no significant electrophysiologic changes, even in aged (16-month-old) mice, suggesting that myelin infoldings and outfoldings per se may not be invariably associated with detectable electrophysiologic abnormalities.
Bolino, A., Brancolini, V., Bono, F., Bruni, A., Gambardella, A., Romeo, G., Quattrone, A., Devoto, M. Localization of a gene responsible for autosomal recessive demyelinating neuropathy with focally folded myelin sheaths to chromosome 11q23 by homozygosity mapping and haplotype sharing. Hum. Molec. Genet. 5: 1051-1054, 1996. [PubMed: 8817346] [Full Text: https://doi.org/10.1093/hmg/5.7.1051]
Bolino, A., Levy, E. R., Muglia, M., Conforti, F. L., LeGuern, E., Salih, M. A. M., Georgiou, D.-M., Christodoulou, R. K., Hausmanowa-Petrusewicz, I., Mandich, P., Gambardella, A., Quattrone, A., Devoto, M., Monaco, A. P. Genetic refinement and physical mapping of the CMT4B gene on chromosome 11q22. Genomics 63: 271-278, 2000. [PubMed: 10673338] [Full Text: https://doi.org/10.1006/geno.1999.6088]
Bolino, A., Muglia, M., Conforti, F. L., LeGuern, E., Salih, M. A. M., Georgiou, D.-M., Christodoulou, K., Hausmanowa-Petrusewicz, I., Mandich, P., Schenone, A., Gambardella, A., Bono, F., Quattrone, A., Devoto, M., Monaco, A. P. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nature Genet. 25: 17-19, 2000. [PubMed: 10802647] [Full Text: https://doi.org/10.1038/75542]
Bolino, A., Seri, M., Caroli, F., Eubanks, J., Srinivasan, J., Mandich, P., Schenone, A., Quattrone, A., Romeo, G., Catterall, W. A., Devoto, M. Exclusion of the SCN2B gene as candidate for CMT4B. Europ. J. Hum. Genet. 6: 629-634, 1998. [PubMed: 9887383] [Full Text: https://doi.org/10.1038/sj.ejhg.5200220]
Bonneick, S., Boentert, M., Berger, P., Atanasoski, S., Mantei, N., Wessig, C., Toyka, K. V., Young, P., Suter, U. An animal model for Charcot-Marie-Tooth disease type 4B1. Hum. Molec. Genet. 14: 3685-3695, 2005. [PubMed: 16249189] [Full Text: https://doi.org/10.1093/hmg/ddi400]
Quattrone, A., Gambardella, A., Bono, F., Aguglia, U., Bolino, A., Bruni, A. C., Montesi, M. P, Oliveri, R. L., Sabatelli, M., Tamburrini, O., Valentino, P., Van Broeckhoven, C., Zappia, M. Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. Neurology 46: 1318-1324, 1996. [PubMed: 8628474] [Full Text: https://doi.org/10.1212/wnl.46.5.1318]
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