Journal
ANNALS OF NEUROLOGY
Volume 69, Issue 6, Pages 1005-1013Publisher
WILEY-BLACKWELL
DOI: 10.1002/ana.22338
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Funding
- Japan Society for the Promotion of Science
- Research on Psychiatric and Neurological Diseases and Mental Health of Health Labor Sciences
- Ministry of Health, Labor, and Welfare [20B-12, 20B-13]
- Japanese Health Sciences Foundation
- National Institute of Biomedical Innovation
- Ministry of Education, Culture, Sports, Science, and Technology (Japan)
- Ministry of Health, Labor, and Welfare (Japan)
- Neuromuscular Foundation (USA)
- Japan Foundation for Neuroscience and Mental Health (indirectly from Genzyme)
- Grants-in-Aid for Scientific Research [21591104] Funding Source: KAKEN
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Objective: Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous muscular disease that presents with muscular dystrophy, joint contractures, and cardiomyopathy with conduction defects. Mutations in several nuclear envelope protein genes have been associated with EDMD in less than half of patients, implying the existence of other causative and modifier genes. We therefore analyzed TMEM43, which encodes LUMA, a newly identified nuclear membrane protein and also a binding partner of emerin and lamins, to investigate whether LUMA may contribute to the pathomechanism of EDMD-related myopathy. Methods: Forty-one patients with EDMD-related myopathy were enrolled. In vitro and in vivo transfection analyses were performed to assay the binding partners and oligomerization of mutant LUMA. Results: We identified heterozygous missense mutations, p. Glu85Lys and p. Ile91Val in TMEM43, in 2 EDMD-related myopathy patients. Reduced nuclear staining of LUMA was observed in the muscle from the patient with p. Glu85Lys mutation. By in vitro transfection analysis, p. Glu85Lys mutant LUMA resulted to failure in oligomerization, a process that may be important for protein complex formation on nuclear membrane. Furthermore, we demonstrated for the first time that LUMA can interact with another nuclear membrane protein, SUN2, in addition to emerin. Cells expressing mutant LUMA revealed reduced nuclear staining with or without aggregates of emerin and SUN2 together with a higher proportion of abnormally shaped nuclei. In vivo expression of mutant LUMA by electroporation in mouse tibialis anterior muscles likewise demonstrated the decreased staining of emerin and SUN2 on myonuclei. Interpretation: Our results suggest that mutant LUMAs may be associated with EDMD-related myopathy. ANN NEUROL 2011;69:1005-1013
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