Genetic heterogeneity in Charcot-Marie-Tooth neuropathy type 2
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Abstract
Charcot-Marie-Tooth neuropathy type 2 (CMT2) is a common inherited axonal neuropathy. The locus for one form of CMT2 (CMT2A) is assigned to the short arm of chromosome 1. There is genetic heterogeneity in CMT2 because additional pedigrees do not demonstrate linkage to chromosome 1 and are designated as CMT2B. Further clinical heterogeneity is suggested by CMT2 pedigrees with diaphragm and vocal cord weakness and are designated as CMT2C. To address the possible genetic distinction between CMT2A and CMT2C, we tested markers from the CMT2A locus for linkage in a large CMT2C pedigree. There was no evidence to support linkage of the CMT2C gene to the region of the CMT2A locus on chromosome 1. CMT2C is not an allelic variant of CMT2A. This analysis provides further evidence for genetic heterogeneity within inherited axonal neuropathies.
NEUROLOGY 1996;46: 569-571
Address correspondence and reprint requests to Dr. Phillip F. Chance, Division of Neurology Research, Room 516G, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 34th and Civic Center Blvd., Philadelphia, PA 19104.
Charcot-Marie-Tooth neuropathy (CMT; also called hereditary motor and sensory neuropathy) is a heterogeneous group of disorders of the peripheral nervous system. CMT type 1 (CMT1) is a demyelinating neuropathy with forms known to map to chromosome 17p11.2-12 (CMT1A), 1q22 (CMT1B), an undetermined autosome (CMT1C), and Xq22 (CMTX) (reviewed in references 1 and 2). CMT2 is an axonal neuropathy and appears to be a less common disorder than CMT1 (all forms combined). Generally, CMT2 may have a later age of onset, less involvement of the hand muscles, and does not have palpably enlarged nerves. Extensive demyelination with ``onion bulb'' formation is not present in CMT2. Motor nerve conduction velocities are normal or only slightly abnormal in affected persons. [2] CMT2 is genetically distinct from all mapped forms of CMT1. A CMT2 locus was assigned by linkage studies to the short arm of chromosome 1 (1p36) and designated as CMT2A. [3] Additional families fulfilling the diagnostic criteria for CMT2 do not have evidence of linkage to this region on chromosome 1, suggesting genetic heterogeneity within CMT2. [3] These pedigrees with axonal neuropathy unlinked to chromosome 1p36 are designated as CMT2B. Further genetic heterogeneity within CMT2 is likely as there are kindreds with the features of axonal neuropathy with diaphragm weakness and vocal cord paralysis that are designated as having CMT2C. [4] In the present report, we examined a CMT2C pedigree for evidence of linkage to chromosome 1p associated with CMT2A. Our analysis in this CMT2C pedigree includes linkage studies with DNA markers mapping within the known CMT2A gene region on chromosome 1.
Methods.
Description of pedigree.
Pedigree K5000 meeting accepted criteria [2] for CMT2 (HMSNII) was studied Figure 1. Affected persons have distal muscle weakness, atrophy, and depressed deep tendon reflexes. Variable pes cavus deformity and degree of sensory loss were present. The median motor nerve conduction velocity in 10 affected persons was more than 50 M/s. [4] Additional details regarding diagnostic criteria and sample collection have been previously reported. [4] Twenty-four subjects, including 11 affected individuals and 9 persons at risk, were investigated. As described in an earlier report, 8 of 11 affected persons gave clinical evidence for diaphragm or vocal cord dysfunction. [4] Male-to-male transmission is apparent, excluding the possibility of X-linked inheritance. Previously, linkage was not detected in pedigree K5000 with markers mapping to the regions of the CMT1A locus on chromosome 17 [5] and the CMT1B locus on chromosome 1. [6] Under a protocol of informed consent (Mayo Clinic), blood samples were obtained by venipuncture. Permanent cell lines were established by Epstein-Barr virus transformation, and high-molecular-weight DNA was isolated from lymphoblasts or leukocytes as previously described. [7]
Figure 1. Pedigree K5000 segregating a gene for CMT2C (HMSNIIc). Females are shown as circles and males as squares. Affected persons are darkened figures. Cross-slashed figures are deceased The analysis included all shown living affected persons.
Genetic markers.
Genotyping was carried out for markers D1S228, D1S199, D1S160, and D1S170 that map to the region of chromosome 1p36 and previously demonstrated linkage in pedigrees with CMT2A. [3] Assays were carried out in 10-mu L reactions containing 25ng of genomic DNA, 2.83 pmol of forward primer (including 0.33 pmol of32 P end-labeled forward primer), 5 pmol of reverse primer, 1 unit of AmpliTaq polymerase, 10 mM Tris, pH 8.3, 50 mM KCl, 1.5 mM MgCl2, and 200 micro Meter of each dNTP. The typical thermal profile was 94 degrees C for 3 minutes, followed by 30 cycles of 94 degrees C for 1 minute, annealing temperature for 2 minutes, and 72 degrees C for 1 minute. Amplified products were fractionated by electrophoresis on 5% or 7% (19:1) polyacrylamide gels containing 5.7 M urea and 32% deionized formamide. The gel was dried, placed against x-ray film, and exposed overnight. The alleles were then scored and the segregation pattern of the various markers were followed.
Linkage analysis.
A linkage analysis was carried out between chromosome 1p36 markers and the mutant CMT2C allele in pedigree K5000. Pairwise LOD score (Z) values, under the assumption of single-gene autosomal dominant inheritance, were calculated with the MLINK option of the computer program LINKAGE (version 5.1). [8] A gene frequency of 0.0001 was assumed for the mutant CMT2C allele, and penetrance was taken as 0.95. At risk, clinically unaffected offspring who were under age 21 years were excluded from linkage calculations. Male and female recombination fractions were assumed to be equal. Multipoint location scores for the CMT2C locus were determined in the region of the D1S228 and D1S199 loci using the LINKMAP option and published map information. [9] Haldane's Equation wasused to convert recombination fractions (theta) to genetic distances (cM). Simulation calculations were carried out in pedigree K5000 to estimate the maximum attainable LOD scores (at zero recombination) with fully informative linkage markers, including affected persons only (Z equals 3.31) and including all persons at risk (Z equals 5.72).
Results.
The results of a pairwise analysis with four markers from the region of the CMT2A locus on chromosome 1p36 are given in the Table 1. All of the LOD scores between CMT2C and these markers are negative and there is no evidence for linkage in this region. The result of a multipoint linkage analysis with the CMT2C locus tested against a fixed genetic map of markers D1S228 and D1S199 is presented in Figure 2. The location score in the region of these two markers is negative, excluding the CMT2C locus from this region of chromosome 1.
Table 1. LOD scores for CMT2C.
Figure 2. Multipoint linkage analysis with markers D1S228 and D1S199 in the region of the CMT2A locus on chromosome 1p36. Location scores (log10 of the odds favoring linkage) are shown on the Y axis and genetic distances (centimorgans) are shown on the X axis. There is no evidence for the CMT2C gene mapping to this region of chromosome 1.
Discussion.
There is marked genetic heterogeneity within inherited disorders of peripheral nerves, including both demyelinating and axonal forms. [1] The results of this analysis confirm genetic heterogeneity that was previously described within axonal neuropathies. The clinical heterogeneity in CMT2 as manifested by the presence of diaphragm and vocal cord weakness in pedigree K5000 suggested that CMT2 might also be genetically heterogeneous. We found no evidence to support linkage of the CMT2C locus to chromosome 1p36, the region previously described for the CMT2A locus. CMT2C is not an allelic variant of CMT2A, and therefore, CMT2A and CMT2C are clinically and genetically distinct disorders. Linkage studies with DNA markers from multiple autosomes will be required to map the CMT2C gene. There may be further genetic heterogeneity within CMT2, as CMT2B and CMT2C may also be distinct disorders. Alternatively, CMT2B and CMT2C possibly may result from mutations at the same locus. The identification of further genetic heterogeneity in CMT2 will await mapping of either CMT2B or CMT2C.
Acknowledgments
The generous cooperation of patients and family members is appreciated. We thank M. William Lensch for technical assistance.
Footnotes
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Received April 21, 1995 Accepted in final form May 30, 1995.
- Copyright 1996 by the Advanstar Communication Inc.
REFERENCES
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Chance PF, Reilly M. Inherited neuropathies. In Thomas PK, ed. Current opinion in neurology. Philadelphia: 1994:372-380.
- 2.↵
Dyck PJ, Chance PF, Lebo RV, Carney JA. Hereditary motor and sensory neuropathies. In Dyck PJ, Thomas PJ, Griffin JW, Low PA, Poduslo JF, eds. Peripheral neuropathy, 3rd ed. Philadelphia: WB Saunders, 1993:1094-1136.
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Ben Othmane K, Middleton LT, Loprest LJ, et al. Localization of a gene for autosomal dominant Charcot-Marie-Tooth type to chromosome 1p and evidence for genetic heterogeneity. Genomics 1993;17:370-375.
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Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 1991;66:219-232.
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Bird TD, Ott J, Giblett ER. Evidence for linkage of Charcot-Marie-Tooth neuropathy to the Duffy locus on chromosome 1. Am J Hum Genet 1982;34:388-394.
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Lathrop GM, Lalouel JM, Julier C, Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet 1985;37:482-498.
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Murray JC, Buetow KH, Weber JL, et al. A comprehensive human linkage map with centimorgan density. Science 1994;265:2049-2054.
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