Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity

K. B. Othmane, L. T. Middleton, L. J. Loprest, K. M. Wilkinson, F. Lennon, M. P. Rozear, J. M. Stajich, P. C. Gaskell, A. D. Roses, Margaret A Pericak-Vance, Jeffery M Vance

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Abstract

Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. We have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analysis and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the 'linked' families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.

Original languageEnglish
Pages (from-to)370-375
Number of pages6
JournalGenomics
Volume17
Issue number2
DOIs
StatePublished - Jan 1 1993
Externally publishedYes

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Charcot-Marie-Tooth Disease
Genetic Heterogeneity
Chromosomes
Genes
Tooth
Lod Score
Phenotype
Chromosomes, Human, Pair 1
Neural Conduction
Pedigree
Age of Onset
Microsatellite Repeats
tetracycline CMT-2

ASJC Scopus subject areas

  • Genetics

Cite this

Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. / Othmane, K. B.; Middleton, L. T.; Loprest, L. J.; Wilkinson, K. M.; Lennon, F.; Rozear, M. P.; Stajich, J. M.; Gaskell, P. C.; Roses, A. D.; Pericak-Vance, Margaret A; Vance, Jeffery M.

In: Genomics, Vol. 17, No. 2, 01.01.1993, p. 370-375.

Research output: Contribution to journalArticle

Othmane, KB, Middleton, LT, Loprest, LJ, Wilkinson, KM, Lennon, F, Rozear, MP, Stajich, JM, Gaskell, PC, Roses, AD, Pericak-Vance, MA & Vance, JM 1993, 'Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity', Genomics, vol. 17, no. 2, pp. 370-375. https://doi.org/10.1006/geno.1993.1334
Othmane, K. B. ; Middleton, L. T. ; Loprest, L. J. ; Wilkinson, K. M. ; Lennon, F. ; Rozear, M. P. ; Stajich, J. M. ; Gaskell, P. C. ; Roses, A. D. ; Pericak-Vance, Margaret A ; Vance, Jeffery M. / Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. In: Genomics. 1993 ; Vol. 17, No. 2. pp. 370-375.
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abstract = "Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. We have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analysis and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the 'linked' families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.",
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AU - Othmane, K. B.

AU - Middleton, L. T.

AU - Loprest, L. J.

AU - Wilkinson, K. M.

AU - Lennon, F.

AU - Rozear, M. P.

AU - Stajich, J. M.

AU - Gaskell, P. C.

AU - Roses, A. D.

AU - Pericak-Vance, Margaret A

AU - Vance, Jeffery M

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N2 - Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. We have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analysis and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the 'linked' families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.

AB - Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. We have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analysis and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the 'linked' families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.

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