TY - JOUR
T1 - Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy
AU - Wallgren-Pettersson, Carina
AU - Pelin, Katarina
AU - Hilpelä, Pirta
AU - Donner, Kati
AU - Porfirio, Berardino
AU - Graziano, Claudio
AU - Swoboda, Kathryn J.
AU - Fardeau, Michel
AU - Urtizberea, J. Andoni
AU - Muntoni, Francesco
AU - Sewry, Caroline
AU - Dubowitz, Victor
AU - Iannaccone, Susan
AU - Minetti, Carlo
AU - Pedemonte, Marina
AU - Seri, Marco
AU - Cusano, Roberto
AU - Lammens, Martin
AU - Castagna-Sloane, Avril
AU - Beggs, Alan H.
AU - Laing, Nigel G.
AU - De La Chapelle, Albert
N1 - Funding Information:
We would like to thank the families with nemaline myopathy for giving their samples for our research, and the following clinicians for diagnosing some of the cases and/or forwarding samples to us: P. Barth, C. Bönnemann, D. Chitayat, A. Clarke, N. Goemans, F. Juul Hansen, F. Hanefeld, H. Hughes, I. Hughes, I. Penisson-Besnier, C. Philippe, I.M. van Langen, H. Marschner-Schäfer, A. Manzur, L. Morandi, G. Rondini, S. Ruyle, J. Sampson, R. Sutphen, C. Vial, M. de Visser, T. Voit, S. Wallace. We thank Dr. Siegfried Labeit, EMBL, Heidelberg, for contributing the marker TTN-AC. We are grateful to the members of the ENMC International Consortium on Nemaline Myopathy for pleasant collaboration. Many members, and other contributors, are acknowledged for collecting samples not used in this study. KP, PH and KD were supported by grants to CWP and AdlC from the Association Francaise contre les Myopathies, the Swedish Cultural Foundation of Finland, the Finska Läkaresällskapet, and the Medicinska understödsföreningen Liv och Hälsa. KJS and AHB were supported by NIH grants AR44345 and AR02026 and by the Muscular Dystrophy Association of the USA. NGL was supported by Australian National Health and Medical Research Council grant 970104. For organisational and financial support to the ENMC International Consortium on Nemaline Myopathy, we are indebted to the European Neuromuscular Centre (ENMC) and its main sponsors: Association Francaise contre les Myopathies (France), Italian Telethon Committee (Italy), Muscular Dystrophy Group of Great Britain and Northern Ireland (UK), Vereniging Spierziekten Nederland (The Netherlands) and Deutsche Gesellschaft für Muskelkranke (Germany), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Prinses Beatrix Fonds (The Netherlands), Verein zur Erforschung von Muskelkrankheiten bei Kindern (Austria) and Muskelsvindfonden (Denmark) as well as its associate members: Unione Italiana Lotta alla Distrofia Muscolare and Muscular Dystrophy Association of Finland. We are also grateful to the ENMC for a separate grant for setting up the ENMC International Database on Nemaline Myopathy.
PY - 1999/12/1
Y1 - 1999/12/1
N2 - Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene. Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations. Copyright (C) 1999 Elsevier Science B.V.
AB - Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene. Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations. Copyright (C) 1999 Elsevier Science B.V.
KW - Autosomal recessive
KW - Clinical forms
KW - Congenital myopathy
KW - Genetic heterogeneity
KW - Genetic loci
KW - Locus heterogeneity
KW - Nemaline (rod) myopathy
KW - Nemaline myopathy
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U2 - 10.1016/S0960-8966(99)00061-9
DO - 10.1016/S0960-8966(99)00061-9
M3 - Article
C2 - 10619714
AN - SCOPUS:0032743263
SN - 0960-8966
VL - 9
SP - 564
EP - 572
JO - Neuromuscular Disorders
JF - Neuromuscular Disorders
IS - 8
ER -