We have constructed a 3.1 megabase (Mb) physical map of chromosome 17p11.2–p12, which contains a submicroscopic duplication in patients with Charcot–Marie–Tooth disease type 1A (CMT1A). We find that the CMT1A duplication is a tandem repeat of 1.5 Mb of DNA. A YAC contig encompassing the CMT1A duplication and spanning the endpoints was also developed. Several low copy repeats in 17p11.2–p12 were identified including the large (> 17 kb) CMT1A–REP unit which may be part of a mosaic repeat. CMT1A–REP flanks the 1.5 Mb CMT1A monomer unit on normal chromosome 17 and is present in an additional copy on the CMT1A duplicated chromosome. We propose that the de novo CMT1A duplication arises from unequal crossing over due to misalignment at these CMT1A–REP repeat sequences during meiosis.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Charcot, J.-M. & Marie, P. Sur une forme particulaiere d'atrophie musculaire progressive souvent familiale debutant par les pied et les jambes et atteignant plus tard les mains. Rev. Med. 6, 97–138 (1886).
Tooth, H.H. The Peroneal Type of Progressive Muscular Atrophy (H.K. Lewis, London, 1886).
Lupski, J.R., Garcia, C.A., Parry, G.J. & Patel, P.I. Charcot-Marie-Tooth Polyneuropathy Syndrome: Clinical Electrophysiological and Genetic Aspects. Current Neurology (ed. Appel, S.) 1–25 (Mosby-Yearbook, Chicago 1991).
Vance, J.M. Hereditary motor and sensory neuropathies. J. med. Genet. 28, 1–5 (1991).
Skre, H. Genetic and clinical aspects of Charcot-Marie-Tooth's disease. Clin. Genet. 6, 98–118 (1974).
Lupski, J.R. & Garcia, C.A. Molecular genetics and neuropathology of Charcot-Marie-Tooth disease type 1A. Brain Pathology 2, 337–349 (1992).
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 neuropathy type 1A (CMT 1A). Neuromusc. Dis. 1, 93–97 (1991).
Wright, E.C., Goldgar, D.E., Fain, P.R., Barker, D.F. & Skolnick, M.H. A genetic map of human chromosome 17p. Genomics 7, 103–109 (1990).
MacMillan, J.C., Upadhyaya, M. & Harper, P.S. Charcot-Marie-Tooth disease 1a(CMT1a): evidence for trisomy of the region p11.2 of chromosome 17 in South Wales families. J. med. Genet. 29, 12–13 (1992).
Hallam, P.J., Harding, A.E., Berciano, J., Barker, D.F. & Malcolm, S. Duplication of part of chromosome 17 is commonly associated with hereditary motor and sensory neuropathy type 1 (Charcot-Marie-Tooth disease type 1). Ann. Neurol. 31, 570–572 (1992).
Lupski, J.R., Pentao, L., Williams, L.L. & Patel, P.I. Stable inheritance of the CMT1A duplication in two patients with CMT1 and NF1. Am. J. med. Genet. (in the press).
Hoogendijk, J.E. et al. De-novo mutation in hereditary motor and sensory neuropathy type 1. 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 (1992).
Suter, U. et al. A leucine-to-proline mutation in the putative 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 (1992).
Snipes, G.J., Suter, U., Welcher, A.A. & Shooter, E.M. Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13). J. cell Biol. 117, 225–238 (1992).
Low, P.A. & McLeod, J.G. Hereditary demyelinating neuropathy in the Trembler mouse. J. neurol. Sci. 26, 565–574 (1975).
Low, P.A. Hereditary hypertrophic neuropathy in the Trembler mouse. Part 1. Histopathological studies: Light microscope. J. neurol. Sci. 30, 327–341 (1976).
Low, P.A. Hereditary hypertrophic neuropathy in the Trembler mouse. Part 2. Histopathological studies: Electron microscope. J. neurol. Sci. 30, 343–368 (1976).
Low, P.A. The evolution of ‘onion bulbs’ in the hereditary hypertrophic neuropathy of the Trembler mouse. Neuropathol. app. Neurobiol. 3, 81–92 (1977).
Low, P.A., McLeod, J.G. & Prineas, J.W. Hypertrophic Charcot-Marie-Tooth disease. Light and electron microscope studies of the sural nerve. J. neurol. Sci. 35, 93–115 (1978).
Low, P.A. & McLeod, J.G. Refractory period, conduction of trains of impulses, and effect of temperature on conduction in chronic hypertrophic neuropathy. J. neurol. Neurosurg. Psych. 40, 434–447 (1977).
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).
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).
Burke, D.T., Carle, G.F. & Olson, M.V. Cloning of large segments of exogenous DNA into yeast by means of artificial chromosome vectors. Science 236, 806–812 (1987).
Brownstein, B.H. et al. Isolation of single-copy human genes from a library of yeast artificial chromosome clones. Science 244, 1348–1351 (1989).
Albertsen, H.M. et al. Construction and characterization of a yeast artificial chromosome library containing seven haploid human genome equivalents. Proc. natn. Acad. Sci. U.S.A. 87, 4256–4260 (1990).
Guzzetta, V. et al. Somatic cell hybrids, sequence tagged sites, simple repeat polymorphisms and yeast artificial chromosomes for physical and genetic mapping of proximal 17p. Genomics 13, 551–559 (1992).
Weber, J.L. et al. Dinucleotide repeat polymorphisms at the D17S250 and D17S261 loci. Nucl. Acids Res. 18, 4640 (1990).
Raeymaekers, P. et al. Estimation of the size of the chromosome 17p11.2 duplication Charcot-Marie-Tooth neuropathy type 1a (CMT1a). J. med. Genet. 29, 5–11 (1992).
Patel, P.I. et al. Isolation of a marker linked to the Charcot-Marie-Tooth disease type 1A gene by differential Alu-PCR of human chromosome 17-retaining hybrids. Am. J. hum. Genet. 47, 926–934 (1990).
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).
van Tuinen, P., Rich, D.C., Summers, K.M. & Ledbetter, D.H. Regional mapping panel for human chromosome 17: Application to neurofibromatosis type 1. Genomics 1, 374–381 (1987).
Patel, P.I. et al. Genetic mapping of autosomal dominant Charcot-Marie-Tooth disease in a large French-Acadian kindred: Identification of new linked markers on chromosome 17. Am. J. hum. Genet. 46, 801–809 (1990).
Bird, A. CpG islands as gene markers in the vertebrate nucleus. Trends Genet. 3, 341–347 (1987).
Hu, X. & Worton, R.G. Partial gene duplication as a cause of human disease. Hum. Mut. 1, 3–12 (1992).
Yen, P.H. et al. Frequent deletions of the human X chromosome distal short arm result from recombination between low copy repetitive elements. Cell 61, 603–610 (1990).
Ballabio, A., Bardoni, B., Guioli, S., Basler, E. & Camerino, G. Two families of low-copy-number repeats are interspersed on Xp22.3: implications for the high frequency of deletions in this region. Genomics 6, 263–270 (1990).
Vollrath, D., Nathans, J. & Davis, R.W. Tandem array of human visual pigment genes at Xq28. Science 240, 1669–1672 (1988).
Nathans, J. et al. Molecular genetics of human blue cone monochromacy. Science 245, 831–838 (1989).
Lupski, J.R., Garcia, C.A., Zoghbi, H.Y., Hoffman, E.P. & Fenwick, R.G. Discordance of muscular dystrophy in monozygotic female twins: Evidence supporting asymmetric splitting of the inner cell mass in a manifesting carrier of Duchenne dystrophy. Am. J. med. Genet. 40, 354–364 (1991).
Hu, X., Ray, P.N., Murphy, E.G., Thompson, M.W. & Worton, R.G. Duplicational mutation at the Duchenne muscular dystrophy locus: Its frequency, distribution, origin, and phenotype genotype correlation. Am. J. hum. Genet. 46, 682–695 (1990).
Darras, B.T. et al. Intragenic deletions in 21 Duchenne muscular dystrophy (BMD)/Becker muscular dystrophy (BMD) families studied with dystrophin cDNA: location of breakpoints on HindIII and BglII exon-containing fragment maps, meiotic and mitotic origin of the mutations. Am. J. hum. Genet. 43, 620–629 (1988).
Kwiatkowski, T.J. Jr., Zoghbi, H.Y., Ledbetter, S.A., Ellison, K.A. & Chinault, A.C. Rapid identification of yeast artificial chromosome clones by matrix pooling and crude lysate PCR. Nucl. Acids Res. 18, 7191 (1990).
Nelson, D.L. et al. Alu polymerase chain reaction: A method for rapid isolation of human-specific sequences from complex DNA sources. Proc. natn. Acad. Sci. U.S.A 86, 6686–6690 (1989).
Riley, J. et al. A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. Nucl. Acids Res. 18, 2887–2890 (1990).
Edwards, A., Civitello, A., Hammond, H.A. & Caskey, C.T. DNA typing and genetic mapping with trimeric and tetrameric tandem repeats. Am. J. hum. Genet. 49, 746–756 (1991).
Breukel, C. et al. Vector-Alu PCR: a rapid step in mapping cosmids and YACs. Nucl. Acids Res. 18, 3097 (1990).
Burmeister, M. et al. A map of the distal region of the long arm of human chromosome 21 constructed by radiation hybrid mapping and pulsed-field gel electrophoresis. Genomics 9, 19–30 (1991).
About this article
Cite this article
Pentao, L., Wise, C., Chinault, A. et al. Charcot–Marie–Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet 2, 292–300 (1992) doi:10.1038/ng1292-292
2018 Victor A. McKusick Leadership Award: Molecular Mechanisms for Genomic and Chromosomal Rearrangements
The American Journal of Human Genetics (2019)
Rescue of recurrent deep intronic mutation underlying cell type–dependent quantitative NEMO deficiency
Journal of Clinical Investigation (2018)
The Nucleus (2017)
Annals of Clinical and Translational Neurology (2017)
Human Genomics (2016)