Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by peroneal and distal muscle atrophy at the extremities. Clinically homogenous, the disorder is separated into two types, CMT 1 and CMT 2. These two types can be differentiated pathologically and physiologically using Nerve Conduction Studies (NCS). We initially localized CMT la to chromosome 17 and have recently sublocalized this form to the 17pll.2 region of chromosome 17. This proposal describes an approach to continue our localization of CMT la. In addition, CMT2 families are identified through our work on CMT la. We also propose to apply linkage analysis to CMT 2 to determine chromosomal location of this disorder. The approach towards localizing the CMT la gene includes expansion of family data, identification of probes using existing libraries (chromosome 17 cosmid library, L4 microcell link library), and the development of new plasmid libraries from chromosome 17 radiation hybrids spanning this region. Multipoint linkage analysis will be used for further localization with these probes until close flanking markers are found. Application of current methodology such as PCR, STS, CA repeats, single strand conformation polymorphisms and nucleotide analog polymorphisms will be used with selected cloned markers to increase heterozygosity of these probes. As close-flanking markers are found, concurrent physical mapping using pulse field gel electrophoresis, cosmid, linkage and hopping libraries and yeast artificial chromosomes will be used to map the region surrounding the CMT la gene. Candidate probes can be screened against zoo blots and a peripheral nerve cDNA library. A similar approach will be applied when the gene for CMT 2 is located.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology C Study Section (NEUC)
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Duke University
Schools of Medicine
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Verhoeven, Kristien; Claeys, Kristl G; Zuchner, Stephan et al. (2006) MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 129:2093-102
Pericak-Vance, M A; Speer, M C; Lennon, F et al. (1997) Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity. Neurogenetics 1:89-93
Othmane, K B; Loeb, D; Hayworth-Hodgte, R et al. (1995) Physical and genetic mapping of the CMT4A locus and exclusion of PMP-2 as the defect in CMT4A. Genomics 28:286-90
Loeb, D B; Pericak-Vance, M A; Stajich, J M et al. (1994) A novel mutation in the von Hippel-Lindau gene. Hum Mol Genet 3:1423-4
Burke, J R; Wingfield, M S; Lewis, K E et al. (1994) The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family. Nat Genet 7:521-4
Denton, P H; Cullen, J B; Loeb, D et al. (1994) Partitioned pulsed-field gel electrophoresis-PCR (PPF-PCR): a new method for pulsed-field mapping for STS and microsatellites. Nucleic Acids Res 22:1776-7
Pericak-Vance, M A; Nunes, K J; Whisenant, E et al. (1993) Genetic mapping of dinucleotide repeat polymorphisms and von Hippel-Lindau disease on chromosome 3p25-26. J Med Genet 30:487-91
Ben Othmane, K; Middleton, L T; Loprest, L J 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 17:370-5
Ben Othmane, K; Hentati, F; Lennon, F et al. (1993) Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet 2:1625-8