Abstract
P0, a major structural protein of peripheral myelin, is a homophilic adhesion molecule and maps to chromosome 1q22–q23, in the region of the locus for Charcot–Marie–Tooth neuropathy type 1B (CMT1B). We have investigated P0 as a candidate gene in two pedigrees with CMT1B and found point mutations which are completely linked with the disease (ẑ=5.5, Θ=0). The mutations, glutamate substitution for lysine 96 or aspartate 90, are located in the extracellular domain, which plays a significant role in myelin membrane adhesion. Individuals with CMT1B are heterozygous for the normal allele and the mutant allele. Our results indicate that P0 is a gene responsible for CMT1B.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dyck, P.J., Chance, P., Lebo, R. & Carney, J.I. Hereditary motor and sensory neuropathies. in Peripheral neuropathy 3rd edn (eds Dyck, P.J. et al.) 1094–1136 (Saunders, Philadelphia, 1993).
Harding, A.E. & Thomas, P.K. Genetic aspects of hereditary motor and sensory neuropathy (type I and II). J. med. Genet. 17, 329–336 (1980).
Bird, T.D., Ott, J. & Giblett, E.R. Evidence for linkage of Charcot-Marie-Tooth disease to the duffy locus on chromosome 1. Am. J. hum. Genet. 34, 388–394 (1982).
Stebbins, N.B. & Conneally, P.M. Linkage of dominantly inherited Charcot-Marie-Tooth neuropathy to the duffy locus in an Indiana family (abstract). Am. J. hum. Genet. 34, 195A (1982).
Vance, J.M. et al. Localization of Charcot-Marie-Tooth disease type 1a (CMT1A) to chromosome 17. Exp. Neurol. 104, 186–189 (1989).
Chance, P.F. et al. Linkage and heterogeneity in type 1 Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy 1). Am. J. hum. Genet. 47, 915–925 (1990).
Chance, P.F., Matsunami, N., Lensch, M.W., Smith, B.S. & Bird, T.D. Analysis of the DNA duplication 17p11.2 in Charcot-Marie-Tooth neuropathy type 1 (HMSN1) pedigrees: Additional evidence for a third autosomal CMT1 locus. Neurology 42, 2037–2041 (1992).
Gal, A. et al. X-linked dominant Charcot-Marie-Tooth disease: suggestion of linkage with a cloned DNA sequence from proximal Xq. Hum. Genet. 70, 38–42 (1985).
Fischbeck, K.H. et al. X-linked neuropathy: gene localization with DNA probes. Ann. Neurol. 20, 527–532 (1986).
Patel, P.I. et al. The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nature Genet. 1, 159–165 (1992).
Timmerman, V. et al. The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication. Nature Genet. 1, 171–175 (1992).
Valentijn, L.J. et al. The peripheral myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A. Nature Genet. 1, 166–170 (1992).
Matsunami, N. et al. Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. Nature Genet. 1, 176–179 (1992).
Valentijn, L.J. et al. Identical point mutations of PMP-22 in trembler-J mouse and Charcot-Marie-Tooth disease type 1A. Nature Genet. 2, 288–291 (1992).
Uyemura, K., Kitamura, K. & Miura, M. Structure and molecular biology of P0 protein. in Myelin: Biology and Chemistry (ed. Martenson, R.) 481–507 (CRC Press, Boca Raton, 1992).
Giese, K.P., Martini, R., Lemke, G., Soriano, P. & Schachner, M. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell 71, 565–576 (1992).
Hayasaka, K. et al. Structure and chromosomal localization of the gene encoding the human myelin protein zero (MPZ). Genomics (in the press).
Oakey, R.J., Watson, M.L. & Seldin, M.F. Construction of a physical map on mouse and human chromosome 1: comparison of 13 Mb of mouse and 11 Mb of human DNA. Hum. molec. Genet. 1, 613–620 (1992).
Hayasaka, K. et al. Isolation and sequence determination of cDNA encoding the major structural protein of human peripheral myelin. Biochem. Biophys. Res. Commun. 180, 515–518 (1991).
Lemke, G., Lamar, E. & Patterson, J. Isolation and analysis of the gene encoding peripheral myelin protein zero. Neuron 1, 73–83 (1988).
Sakamoto, Y., Kitamura, K., Yoshimura, K., Nishijima, T. & Uyemura, K. Complete amino acid sequence of P0 protein in bovine peripheral nerve myelin. J. biol. Chem. 262, 4208–4214 (1987).
Lemke, G. & Axel, R. Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 40, 501–508 (1985).
Barbu, M. Molecular cloning of cDNAs that encodes the chicken P0 protein: evidence for early expression in avian. J. neurosci. Res. 25, 143–151 (1990).
Garnier, J., Osguthorpe, D.J. & Robson, B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J. molec. Biol. 120, 97–120 (1978).
Ionasescu, V.V., Trofatter, J., Haines, J.L., Ionasescu, R. & Searby, C. Charcot-Marie-Tooth neuropathy related to chromosome 1. Am. J. med. Genet. 42, 728–732 (1992).
Defesche, J.C., Hoogendijk, J.E., De Visser, M., Ongerboer de Visser, B.M. & Bolhuis, P.A. Genetic linkage of hereditary motor and sensory neuropathy type I (Charcot-Marie-Tooth disease) to markers of chromosomes 1 and 17. Neurology 40, 1450–1453 (1990).
Kulkens, et al. Nature Genet. (in the press).
Lebo, R.V. et al. Chromosome 1 Charcot-Marie-Tooth disease (CMT1B) locus in Fcγ receptor gene region. Hum. Genet. 88, 1–12 (1991).
Kunkel, L.M. et al. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc. natn. Acad. Sci. U.S.A. 74, 1245–1249 (1977).
Misiura, K., Durrant, I., Evans, M.R. & Gait, M.J. Biotinyl and phosphoramide derivatives useful in the incorporation of multiple reporter groups on synthetic oligonucleotides. Nucl. Acids Res. 18, 4345–4354 (1990).
Espelund, M., Prentice Stacy, R.A. & Jakobsen, K.S. A simple method for generating single-stranded DNA probes labeled to high activities. Nucl. Acids Res. 20, 6157–6158 (1990).
Sanger, F., Nicklen, S. & Coulson, A.R. DNA sequencing with chain-terminating inhibitors. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).
Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. hum. Genet. 37, 482–498 (1985).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hayasaka, K., Himoro, M., Sato, W. et al. Charcot–Marie–Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene. Nat Genet 5, 31–34 (1993). https://doi.org/10.1038/ng0993-31
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0993-31
This article is cited by
-
Mechanisms and Treatments in Demyelinating CMT
Neurotherapeutics (2021)
-
Electron Microscopy Analysis of Sciatic Nerve Fibers in C57BL/6 Transgenic Mice
Neurophysiology (2020)
-
Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia
Nature Genetics (2019)
-
Phylogenetically Conserved Sequences Around Myelin P0 Stop Codon are Essential for Translational Readthrough to Produce L-MPZ
Neurochemical Research (2018)
-
In silico analysis of autoimmune diseases and genetic relationships to vaccination against infectious diseases
BMC Immunology (2014)