X-linked recessive myotubular myopathy (MTM1) is characterized by severe hypotonia and generalized muscle weakness, with impaired maturation of muscle fibres. We have restricted the candidate region to 280 kb and characterized two candidate genes using positional cloning strategies. The presence of frameshift or missense mutations (of which two are new mutations) in seven patients proved that one of these genes is indeed implicated in MTM1. The protein encoded by the MTM1 gene is highly conserved in yeast, which is surprising for a muscle specific disease. The protein contains the consensus sequence for the active site of tyrosine phosphatases, a wide class of proteins involved in signal transduction. At least three other genes, one located within 100 kb distal from the MTM1 gene, encode proteins with very high sequence similarities and define, together with the MTM1 gene, a new family of putative tyrosine phosphatases in man.
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Wallgren-Pettersson, C. & Thomas, N. Report on the 20th ENMC sponsored international workshop: myotubular/centronuclear myopathy. Neuromusc.Descord. 4, 71–74 (1994).
Fardeau, M., Congential Myopathy in Skeletal muscle Pathology (eds Mastaglia, F.L & Walton of Detchant) (Edinburgh, Churchill Livingstone, 1992).
Sarnat, H.B., Myopathy: arrest of morphogenesis of myofibers associated with persistence of fetal vimentine and desmin Four cases compared with fetal and neonatal muscle. Can. J. Neurol. Sci. 17, 109–123 (1990).
Sawchak, J.A., Sher, J.H., Norman, M.G., Kula, R.W. & Shafiq, S.A. Centronuclear myopathy heterogeneity: distinction of clinical types by myosin isoform patterns. Neurol. 41, 135–140 (1991).
Wallgren-Pettersson, C. et al. The Myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DMA studies. J. Med. Genet. 32, 673–679 (1995).
Heckmatt, J.Z., Sewry, C.A., Hodes, D. & Dubowitz, V. Congenital centronuclear (myotubular) myopathy: a clinical, pathological and genetic study in eight children. Brain 108, 941–064 (1985).
Thomas, N. et al. X-linked centronuclear/myotubular myopathy: evidence for linkage to Xq28 DMA marker loci. J. Med. Genet. 27, 284–287 (1990).
Damfors, C. et al. X-linked myotubular myopathy: a linkage study. Clin. Genet. 37, 335–340 (1990).
Lehesjoki, A.E. et al. X-linked neonatal myotubular myopathy: one recombination detected with four polymorphic DMA markers from Xq28. J. Med. Genet. 27, 288–291 (1990).
Start, J., Lamont, M., L, Harvey, J.& Heckmatt, J. A linkage study of a large pedigree with X-linked centronuclear myopathy. J. Med. Genet. 27, 281–283 (1990).
Liechti-Gallati, S. et al. X-linked centronuclear myopathy: mapping the gene to Xq28. Neuromusc. Disord. 4, 239–245 (1991).
Janssen, E.A. et al. The gene for X-linked myotubular myopathy is located in an 8 Mb region at the border of Xq27. 3 and Xq28. Neuromusc. Disord. 4, 455–461 (1994).
Dahl, N. et al. X linked myotubular myopathy (MTM1) maps between DXS304 and DXS305, closely linked to the DXS455 VNTR and a new, highly informative microsatellite marker (DXS1684). J. Med. Genet. 31, 922–924 (1994).
Dahl, N. et al.Myotubular myopathy in a girl with a deletion at Xq27–q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region. Am. J. Hum. Genet. 56, 1108–1115 (1995).
Hu, L.J. et al. Deletions in Xq28 in two boys with Myotubular myopathy and abnormal genital development define a new contiguous gene syndrome in a 430kb region. Hum. Mol. Genet. 5, 139–143 (1996).
Kioschis, P. et al. A 900-kb cosmid contig and 1 à new transcripts within the candidate region for myotubular myopathy (MTM1). Genomics (in the press).
Hu, L.J. et al. X-linked myotubular myopathy: refinement of the gene to a 280 kb region with new and highly informative microsatellite markers. Hum. Genet. (in the press).
Korn, B. et al. A strategy for the selection of transcribed sequences in Xq28 region. Hum. Mol. Genet. 4, 235–242 (1992).
Sedlacek, Z. et al. Construction of a 300 kb region around the human G6PD locus by direct cDNA selection. Hum. Mol. Genet. 11, 1865–1869 (1993).
Buckler, A.J. et al. Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc. NaU. Acad. Sci. USA 88, 4005–4009 (1991).
Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DMA using exon amplification. Nature Genet. 6, 98–105 (1994).
Andersson, B., Lu, F., Muzny, D.M. & Gibbs, R.A. Complete sequence of a 38. 4-kb human cosmid insert containing the polymorphic marker DXS455 from Xq28. DNASeq. 5, 219–223 (1995).
Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in humanDNA sequences by a multiple sensor-neural approach. Proc. Natl. Acad. Sci. USA 88, 11261–11265 (1991).
Xu, Y., Mural, R., Shah, M. & Uberbacher, E. Recognizing exons in genomic sequence using GRAIL II. Genet. Eng. (N. Y.) 16, 241–253 (1994).
Solovyev, V.V., Salamov, A.A. & Lawrence, C.B. Predicting internal exons by oligonucleotide composition and discriminant analysis of spliceable open reading frames. Nucl. Acids Res. 22, 5156–5163 (1994).
Gregg, R.G., Metzenberg, A.B., Hogan, K., Sekhon, G. & Laxova, R. Waisman syndrome, a human X-linked recessive basal ganglia disorder with mental retardation: localization toXq27 3-qter. Genomics 9, 701–706 (1991).
Gedeon, A., Kerr, B., Mulley, J. & Turner, G. Localisation of the MRX3 gene for non-specific X linked mental retardation. J. Med. Genet. 28, 372–377 (1991).
Biancalana, V., Le Marec, B., Odent, S., Van den Hurk, J.A.M.J. & Hanauer, A. Oto-palato-digital syndrome type I: further evidence for assignement of the locus to Xq28. Hum. Genet. 88, 228–230 (1991).
Palmieri, G. et al. YAC contig organization and CpG island analysis in Xq28. Genomics 24, 149–158 (1994).
Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basis local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).
Fischer, E.H., Charbonneau, H. & Tonks, N.K. Proteintyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science 253, 401–406 (1991).
Mourey, R.J. & Dixon, J.E. Protein tyrosine phosphatases: characterization of extracellular and intracellular domains. Curr. Opin. Genet. Dev. 4, 31–39 (1994).
Mosser, J. et al. Putative X-linked adrendeukodystrophy gene shares unexpected homdogy with ABC transporters. Nature 361, 726–730 (1993).
Bronner, C.E. et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-pdyposis colon cancer. Nature 368, 258–261 (1994).
Tugendreich, S., Bassett, D.E., McKusick, V.A., Boguski, M.S. & Hieter, R. Genes conserved in yeast and humans. Hum. Mol. Genet. 3, 1509–1517 (1994).
Tonks, N.K. Introduction: protein tyrosine phosphatases. Semin. Cell Biol. 4, 373–377 (1993).
Samson, F. et al. Genetic linkage heterogeneity in myotubular myopathy. Am. J. Hum. Genet. 57, 120–126 (1995).
Donoghue, M.J. & Sanes, J.R. All muscles are not created equal. Trends. Genet. 10, 39–6401 (1994).
Florini, J.R., Ewton, D.Z. & Magri, K.A., Hormones, growth factors, and myogenic differentiation. Annu. Rev. Physiol. 53, 201–216 (1991).
Valenzuela, D.M. et al. Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Neuron 15, 573–584 (1995).
Rastinejad, F., Conboy, M.J., Rando, T.A. & Blau, H.M. Tumor suppression by RNA from the 3′ untranslated region of alpha-tropomyosin. Cell 75, 1107–1117 (1993).
Miller, S., Dykes, D. & Polesky, H. A simple salting out method for extracting DNA from human nucleated cells. Nucl. Acids Res. 16, 1215 (1988).
Oberie, I. et al. Characterization of a set of X-linked sequences and of a panel of somatic cell hybrids useful for the regional mapping of the human X chromosome. Hum. Genet. 72, 43–49 (1986).
Berry, R. et al. Gene-based sequence-tagged-sites (STSs) as the basis for a human gene map. Nature Genet. 10, 415–423 (1995).
Lanfranchi, G. et al. Identification of 4,370 expressed sequence tags (ESTs) from a 3′-end specific cDNA library of human skeletal muscle by DNA sequencing and fitter hybridization. Genome Res. (in the press).
Castilla, L.H. et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nature Genet. 8, 387–391 (1994).
Wilson, R. et al. 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature 368, 32–38 (1994).
Gribskov, M. & Burgess, R.R. Sigma factors from E. coli, B. subtilis, phage SP01, and phage T4 are homologous proteins. Nucl. Acids Res. 14, 6745–6763 (1986).
Lan, M.S., Lu, J., Goto, Y. & Notkins, A.L. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol. 13, 505–514 (1994).
Yang, Q. & Tonks, N.K. Isolation of a cDNA clone encoding a human protein-tyrosine phosphatase with homology to the cytoskeletal-associated proteins band 4 1, erzin, and talin. Proc. Natl. Acad. Sci. USA 88, 5949–5953 (1991).
Streuli, M., Krueger, N.X., Tsai, A.Y.M. & Saito, H. A family of receptor-linked protein tyrosine phosphatases in humans and Drosophila. Proc. Natl. Acad. Sci. USA 86, 8698–6702 (1989).
Mauro, L.J. et al. Identification of a hormonally regulated protein tyrosine phosphatase associated with bone and testicular differenciation. J. Biol. Chem. 269, 30659–30667 (1994).
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Journal of Neuromuscular Diseases (2019)
Muscle & Nerve (2019)
Seminars in Pediatric Neurology (2019)
Seminars in Pediatric Neurology (2019)
Human Molecular Genetics (2019)