Abstract
We have investigated the peripheral myelin protein gene, PMP–22, in a family with Charcot–Marie–Tooth disease type 1A (CMT1A). The DNA duplication commonly found in CMT1A was absent in this family, but strong linkage existed between the disease and the CMT1A marker VAW409R3 on chromosome 17p11.2. We found a point mutation in PMP–22 which was completely linked with the disease. The mutation, a proline for leucine substitution in the first putative transmembrane domain, is identical to that recently found in the Trembler–J mouse. The presence of this PMP–22 defect in this CMT1A family and the location of PMP–22 within the DNA duplication associated with CMT1A suggest that both structural alteration and overexpression of PMP–22 may lead to the disease.
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
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Harding, A.E. & Thomas, P.K. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103, 259–280 (1980).
Hoogendijk, J.E. & De Visser, M. in Handbook of Clinical Neurology. Hereditary neuropathies and spinocerebellar atrophies. Vol. 60 (eds Vinken, P.J. et al.).(Elsevier, Amsterdam, 1991).
Vance, J.M. et al. Linkage of Charcot-Marie-Tooth neuropathy type 1a to chromosome 17. Exp. Neurology. 104, 186–189 (1989).
Vance, J.M. et al. Localization of Charcot-Marie-Tooth disease type 1a (CMT1A) to chromosome 17p11.2. Genomics 9, 623–628 (1991).
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).
Lebo, V.L. et al. Chromosome 1 Charcot-Marie-Tooth disease (CMT1B) locus in the Fcγ receptor gene region. Hum. Genet. 88, 1–12 (1991).
Lupski, J.R. et al. DNA duplication associated with Charcot-Marie-Tooth Disease type 1a. Cell 66, 219–232 (1991).
Raeymaekers, P. et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth disease type 1a (CMT1A). Neuromusc. Dis. 1, 93–97 (1991).
Hoogendijk, J.E. et al. The duplication in Charcot-Marie-Tooth disease type 1 a spans at least 1100 kb on chromosome 17p11.2. Hum. Genet. 88, 215–218 (1991).
Raeymaekers, P. et al. Estimation of the size of the chromosome 17p11.2 duplication in Charcot-Marie-Tooth neuropathy type 1a (CMT1A). J. med. Genet. 29, 5–11 (1992).
Hoogendijk, J.E. et al. De novo mutation in heditary motor and sensory neuropathy type I. Lancet 339, 1081–1082 (1992).
Lupski, J.R. et al. Gene dosage is a mechanism for Charcot-Marie-Tooth Disease type 1A. Nature Genet. 1, 29–33 (1992).
Suter, U. et al. Trembler mouse carries a point mutation in a myelin gene. Nature 356, 241–244 (1992a).
Suter, U. et al. A leucine-to-proline mutation in the first transmembrane domain of the 22-kDa peripheral myelin protein in the trembler-J mouse. Proc. natn. Acad. Sci. U.S.A. 89, 4382–4386 (1992b).
Patel, I.P. 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).
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).
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).
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).
Hoogendijk, J.E. et al. Allelic heterogeneity in hereditary motor and sensory neuropathy type 1A (Charcot-Marie-Tooth disease type 1A). Neurology (in the press).
Schneider, C., King, R.M. & Philipson, L. Genes specifically expressed at growth arrest of mammalian cells. Cell 54, 787–793 (1988).
Manfioletti, G., Ruaro, M.E., Del Sal, G., Pilipson, L. & Schneider, C. A growth arrest-specific (gas) gene codes for a membrane protein. Molec. cell. Biol. 10, 2924–2930 (1990).
Spreyer, P. et al. Axon-regulated expression of a Schwann cell transcript that is homologous to a ‘growth arrest-specific’ gene. EMBO. J. 10, 3661–3668 (1991).
Welcher, A.A., Suter, U., De Leon, M., Snipes, G.J. & Shooter, E.M. A myelin protein is encoded by the homologue of a growth arrest-specific gene. Proc. natn Acad. Sci. U.S.A. 88, 7195–7199 (1991).
Schneider, A. et al. Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene. Nature 358, 158–761 (1992).
Hudson, L.D., Pucket, C., Berndt, J., Chan, J. & Gencic, S. Mutation of the proteolipid protein gene PLP in human X chromosome-linked myelin disorder. Proc. natn. Acad. Sci. U.S.A. 86, 8128–8131 (1989).
Gencic, S., Abuelo, D., Ambler, M. & Hudson, L.D. Pelizaeus-Merzbacher disease: An X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am. J. hum. Genet. 45, 435–442 (1989).
Cremers, F.P.M. et al. An interstitial duplication of the X chromosome in a male allows physical fine mapping of probes from the Xq13-q22 region. Hum. Genet. 77, 23–27 (1987).
Greenberg, F. et al. Molecular analysis of the Smith-Magenis Syndrome: A Possible contiguous-gene syndrome associated with del(17)(p11.2). Am. J. hum. Genet. 49, 1207–1218 (1991).
Chou, P.Y. & Fasman, G.D. Prediction of protein conformation. Biochemistry 13, 222–245 (1974).
Gabreëls-Festen, A.A.W.M. et al. Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I). J. neurol. Sci. 107, 145–154 (1992).
Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular cloning. A laboratory manual. 2nd edn (Cold Spring Harbor Labatory Press, New York, 1989).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Valentijn, L., Baas, F., Wolterman, R. et al. Identical point mutations of PMP–22 in Trembler–J mouse and Charcot–Marie–Tooth disease type 1A. Nat Genet 2, 288–291 (1992). https://doi.org/10.1038/ng1292-288
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1292-288