Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy

Persistent Link:
http://hdl.handle.net/10150/610251
Title:
Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy
Author:
Lawlor, Michael; Ottenheijm, Coen; Lehtokari, Vilma-Lotta; Cho, Kiyomi; Pelin, Katarina; Wallgren-Pettersson, Carina; Granzier, Henk; Beggs, Alan
Affiliation:
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
Issue Date:
2011
Publisher:
BioMed Central
Citation:
Lawlor et al. Skeletal Muscle 2011, 1:23 http://www.skeletalmusclejournal.com/content/1/1/23
Journal:
Skeletal Muscle
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)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
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.
EISSN:
2044-5040
DOI:
10.1186/2044-5040-1-23
Keywords:
congenital myopathy; nemaline myopathy; nemaline rod (body); thin filament; nebulin
Version:
Final published version
Additional Links:
http://www.skeletalmusclejournal.com/content/1/1/23

Full metadata record

DC FieldValue Language
dc.contributor.authorLawlor, Michaelen
dc.contributor.authorOttenheijm, Coenen
dc.contributor.authorLehtokari, Vilma-Lottaen
dc.contributor.authorCho, Kiyomien
dc.contributor.authorPelin, Katarinaen
dc.contributor.authorWallgren-Pettersson, Carinaen
dc.contributor.authorGranzier, Henken
dc.contributor.authorBeggs, Alanen
dc.date.accessioned2016-05-20T09:02:13Z-
dc.date.available2016-05-20T09:02:13Z-
dc.date.issued2011en
dc.identifier.citationLawlor et al. Skeletal Muscle 2011, 1:23 http://www.skeletalmusclejournal.com/content/1/1/23en
dc.identifier.doi10.1186/2044-5040-1-23en
dc.identifier.urihttp://hdl.handle.net/10150/610251-
dc.description.abstractBACKGROUND: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.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.skeletalmusclejournal.com/content/1/1/23en
dc.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)en
dc.subjectcongenital myopathyen
dc.subjectnemaline myopathyen
dc.subjectnemaline rod (body)en
dc.subjectthin filamenten
dc.subjectnebulinen
dc.titleNovel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathyen
dc.typeArticleen
dc.identifier.eissn2044-5040en
dc.contributor.departmentDivision 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, USAen
dc.contributor.departmentDepartment of Physiology, University of Arizona, 1501 N. Campbell, Rm. 4104, Tucson, AZ, 85724, USAen
dc.contributor.departmentLaboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlandsen
dc.contributor.departmentThe Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, P.O. Box 63 (Haartmaninkatu 8), FI-00014, University of Helsinki, Helsinki, Finlanden
dc.contributor.departmentDivision of Genetics, Department of Biosciences, P.O. Box 56 (Viikinkaari 9), FI-00014, University of Helsinki, Helsinki, Finlanden
dc.identifier.journalSkeletal Muscleen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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