FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 329:96-101 July 8, 1993 Number 2 Next

	Full Text Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase (Mb) DNA duplication in region p11.2-p12 of chromosome 17 in most patients. An increased dosage of a gene within the duplicated segment appears to cause the disease. The PMP22 gene, which encodes a myelin protein, has been mapped within the duplication and proposed as a candidate gene for CMT type 1A.

Methods We analyzed DNA samples from a cohort of 32 unrelated patients with CMT type 1 who did not have the 1.5-Mb tandem duplication in 17p11.2-p12 for mutations within the PMP22 coding region. Molecular techniques included the polymerase chain reaction (PCR), heteroduplex analysis to detect point mutations, and direct nucleotide-sequence determination of amplified PCR products.

Results A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22. Analysis of family members revealed that the PMP22 point mutation arose spontaneously and segregated with the CMT type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotypes that were similar to those of patients with the 1.5-Mb duplication.

Conclusions The PMP22 gene has a causative role in CMT type 1. Either a point mutation in PMP22 or a duplication of the region including the PMP22 gene can result in the disease phenotype.

Source Information

From the Institute for Molecular Genetics (B.B.R., D.A.K., C.A.W., P.I.P., J.R.L.), Human Genome Center (P.I.P., J.R.L.), and Department of Pediatrics (J.R.L.), Baylor College of Medicine, Houston; the Departments of Neurology (C.A.G., J.M.) and Pathology (C.A.G.), Louisiana State University School of Medicine, New Orleans; the Departments of Neurobiology (U.S., A.A.W., G.J.S., E.M.S.) and Neuropathology (G.J.S.), Stanford University School of Medicine, Stanford, Calif.; and the Department of Cell Biology, Swiss Federal Institute of Technology, ETH Honggerberg Zurich, Switzerland (U.S.).

Address reprint requests to Dr. Lupski at the Institute for Molecular Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030-3498.

Full Text of this Article

This article has been cited by other articles:

• Bellone, E, Balestra, P, Ribizzi, G, Schenone, A, Zocchi, G, Di Maria, E, Ajmar, F, Mandich, P (2006). An abnormal mRNA produced by a novel PMP22 splice site mutation associated with HNPP. J. Neurol. Neurosurg. Psychiatry 77: 538-540 [Abstract] [Full Text]  
• Glaser, R. L., Jabs, E. W. (2004). Dear Old Dad. Sci Aging Knowl Environ 2004: re1-re1 [Abstract] [Full Text]  
• Orejana-Garcia, A. M., Pascual-Huerta, J., Perez-Melero, A. (2003). Charcot-Marie-Tooth Disease and Vincristine. J. Am. Podiatr. Med. Assoc. 93: 229-233 [Abstract] [Full Text]  
• Sambuughin, N., de Bantel, A., McWilliams, S., Sivakumar, K. (2003). Deafness and CMT disease associated with a novel four amino acid deletion in the PMP22 gene. Neurology 60: 506-508 [Abstract] [Full Text]  
• Street, V. A., Bennett, C. L., Goldy, J. D., Shirk, A. J., Kleopa, K. A., Tempel, B. L, Lipe, H. P., Scherer, S. S., Bird, T. D., Chance, P. F. (2003). Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology 60: 22-26 [Abstract] [Full Text]  
• McEntagart, M, Dunstan, M, Bell, C, Boltshauser, E, Donaghy, M, Harper, P S, Williams, N, Teare, M D, Rahman, N (2002). Clinical and genetic heterogeneity in peroneal muscular atrophy associated with vocal cord weakness. J. Neurol. Neurosurg. Psychiatry 73: 762-765 [Abstract] [Full Text]  
• Sancho, S., Young, P., Suter, U. (2001). Regulation of Schwann cell proliferation and apoptosis in PMP22-deficient mice and mouse models of Charcot-Marie-Tooth disease type 1A. Brain 124: 2177-2187 [Abstract] [Full Text]  
• Fabrizi, G M, Simonati, A, Taioli, F, Cavallaro, T, Ferrarini, M, Rigatelli, F, Pini, A, Mostacciuolo, M L, Rizzuto, N (2001). PMP22 related congenital hypomyelination neuropathy. J. Neurol. Neurosurg. Psychiatry 70: 123-126 [Abstract] [Full Text]  
• Brancolini, C., Edomi, P., Marzinotto, S., Schneider, C. (2000). Exposure at the Cell Surface Is Required for Gas3/PMP22 To Regulate Both Cell Death and Cell Spreading: Implication for the Charcot-Marie-Tooth Type 1A and Dejerine-Sottas Diseases. Mol. Biol. Cell 11: 2901-2914 [Abstract] [Full Text]  
• Isaacs, A. M., Davies, K. E., Hunter, A. J., Nolan, P. M., Vizor, L., Peters, J., Gale, D. G., Kelsell, D. P., Latham, I. D., Chase, J. M., Fisher, E. M.C., Bouzyk, M. M., Potter, A., Masih, M., Walsh, F. S., Sims, M. A., Doncaster, K. E., Parsons, C. A., Martin, J., Brown, S. D.M., Rastan, S., Spurr, N. K., Gray, I. C. (2000). Identification of two new Pmp22 mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy. Hum Mol Genet 9: 1865-1871 [Abstract] [Full Text]  
• NADAL, M., VALIENTE, A., DOMÈNECH, A., PRITCHARD, M., ESTIVILL, X., RAMOS-ARROYO, M. A. (2000). Hereditary neuropathy with liability to pressure palsies: two cases with a reciprocal translocation t(16;17)(q12;p11.2) interrupting the PMP22 gene. J. Med. Genet. 37: 396-398 [Full Text]  
• Sander, S, Ouvrier, R A, McLeod, J G, Nicholson, G A, Pollard, J D (2000). Clinical syndromes associated with tomacula or myelin swellings in sural nerve biopsies. J. Neurol. Neurosurg. Psychiatry 68: 483-488 [Abstract] [Full Text]  
• De Jonghe, P., Timmerman, V., Nelis, E., De Vriendt, E., Lofgren, A., Ceuterick, C., Martin, J.-J., Van Broeckhoven, C. (1999). A Novel Type of Hereditary Motor and Sensory Neuropathy Characterized by a Mild Phenotype. Arch Neurol 56: 1283-1288 [Abstract] [Full Text]  
• Fabrizi, G. M., Cavallaro, T., Taioli, F., Orrico, D., Morbin, M., Simonati, A., Rizzuto, N. (1999). Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22. Neurology 53: 846-846 [Abstract] [Full Text]  
• Brancolini, C., Marzinotto, S., Edomi, P., Agostoni, E., Fiorentini, C., Müller, H. W., Schneider, C. (1999). Rho-dependent Regulation of Cell Spreading by the Tetraspan Membrane Protein Gas3/PMP22. Mol. Biol. Cell 10: 2441-2459 [Abstract] [Full Text]  
• North, K. (1999). NEW PERSPECTIVES IN PEDIATRIC NEUROMUSCULAR DISORDERS Hotel Intercontinental Sydney, Sydney, Australia, August 28, 1998. J Child Neurol 14: 26-57  
• Chang, J.-G., Jong, Y.-J., Wang, W.-P., Wang, J.-C., Hu, C.-J., Lo, M.-C., Chang, C.-P. (1998). Rapid detection of a recombinant hotspot associated with Charcot–Marie–Tooth disease type 1A duplication by a PCR-based DNA test. Clin. Chem. 44: 270-274 [Abstract] [Full Text]  
• Pareek, S., Notterpek, L., Snipes, G. J., Naef, R., Sossin, W., Laliberte, J., Iacampo, S., Suter, U., Shooter, E. M., Murphy, R. A. (1997). Neurons Promote the Translocation of Peripheral Myelin Protein 22 into Myelin. J. Neurosci. 17: 7754-7762 [Abstract] [Full Text]  
• Bolin, L. M., McNeil, T., Lucian, L. A., DeVaux, B., Franz-Bacon, K., Gorman, D. M., Zurawski, S., Murray, R., McClanahan, T. K. (1997). HNMP-1: A Novel Hematopoietic and Neural Membrane Protein Differentially Regulated in Neural Development and Injury. J. Neurosci. 17: 5493-5502 [Abstract] [Full Text]  
• Magyar, J. P., Martini, R., Ruelicke, T., Aguzzi, A., Adlkofer, K., Dembic, Z., Zielasek, J., Toyka, K. V., Suter, U. (1996). Impaired Differentiation of Schwann Cells in Transgenic Mice with Increased PMP22 Gene Dosage. J. Neurosci. 16: 5351-5360 [Abstract] [Full Text]  
• Ouvrier, R. (1996). Correlation Between the Histopathologic, Genotypic, and Phenotypic Features of Hereditary Peripheral Neuropathies in Childhood. J Child Neurol 11: 133-146 [Abstract]  
• Taylor, V., Welcher, A. A., Program, A. E., Suter, U. (1995). Epithelial Membrane Protein-1, Peripheral Myelin Protein 22, and Lens Membrane Protein 20 Define a Novel Gene Family. J. Biol. Chem. 270: 28824-28833 [Abstract] [Full Text]  
• Fabbretti, E, Edomi, P, Brancolini, C, Schneider, C (1995). Apoptotic phenotype induced by overexpression of wild-type gas3/PMP22: its relation to the demyelinating peripheral neuropathy CMT1A.. Genes Dev. 9: 1846-1856 [Abstract]  
• Bergoffen, J, Scherer, S., Wang, S, Scott, M., Bone, L., Paul, D., Chen, K, Lensch, M., Chance, P., Fischbeck, K. (1993). Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262: 2039-2042 [Abstract]