Distal myopathy caused by homozygous missense mutations in the nebulin gene
1Department of Medical Genetics, University of Helsinki, 2The Folkhälsan Institute of Genetics, 3Department of Pathology, University of Helsinki, 4Department of Pathology, University of Turku, Finland, 5Department of Pediatrics, Hammersmith Hospital, Imperial College Faculty of Medicine, Hammersmith Hospital, London, Centre for Inherited Neuromuscular Disorders, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK, 6Department of Biological and Environmental Sciences, University of Helsinki, and 7Departments of Neurology, Vasa Central Hospital and University of Tampere, Finland
Correspondence to: Carina Wallgren-Pettersson, M.D., The Folkhälsan Department of Medical Genetics, P.O. Box 211, FIN-00251 Helsinki, Finland E-mail: carina.wallgren{at}helsinki.fi
We describe a novel, recessively inherited distal myopathy caused by homozygous missense mutations in the nebulin gene (NEB), in which other combinations of mutations are known to cause nemaline (rod) myopathy (NM). Two different missense mutations were identified in homozygous form in seven Finnish patients from four unrelated families with childhood or adult-onset foot drop. Both mutations, when combined in compound heterozygous form with more disruptive mutations in NEB, are known to cause NM. Hitherto, no patients with NM have been found to have two missense mutations in NEB. Muscle weakness predominantly affected ankle dorsiflexors, finger extensors and neck flexors, a distribution different both from the patterns of weakness seen in NM caused by NEB mutations, and those of the known recessively inherited distal myopathies. Singleton cases need to be distinguished from the Laing type of distal myopathy. Histologically, this myopathy differs from NM in that nemaline bodies were not detectable with routine light microscopy, and they were inconspicuous or absent even with electron microscopy. Rimmed vacuoles, commonly seen in other distal myopathies, were not a feature. We conclude that homozygous missense mutations in NEB cause a novel distal myopathy, predominantly involving lower leg extensor muscles, finger extensors and neck flexors.
Key Words: distal myopathy; nebulin gene; mutation; missense; recessive
Abbreviations: NEB, nebulin gene; NM, nemaline myopathy; TMD, Tibial muscular dystrophy
Received January 24, 2007. Revised February 22, 2007. Accepted March 26, 2007.
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