BACKGROUND:Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases.RESULTS:We describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.CONCLUSIONS:Our findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/610251 |
| Date | January 2011 |
| Creators | Lawlor, Michael, Ottenheijm, Coen, Lehtokari, Vilma-Lotta, Cho, Kiyomi, Pelin, Katarina, Wallgren-Pettersson, Carina, Granzier, Henk, Beggs, Alan |
| Contributors | Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, CLSB 15026, Boston, MA 02115, USA, Department of Physiology, University of Arizona, 1501 N. Campbell, Rm. 4104, Tucson, AZ, 85724, USA, Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands, The Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, P.O. Box 63 (Haartmaninkatu 8), FI-00014, University of Helsinki, Helsinki, Finland, Division of Genetics, Department of Biosciences, P.O. Box 56 (Viikinkaari 9), FI-00014, University of Helsinki, Helsinki, Finland |
| Publisher | BioMed Central |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © 2011 Lawlor et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) |
| Relation | http://www.skeletalmusclejournal.com/content/1/1/23 |
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