期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 11, 页码 4693-4708出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI75199
关键词
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资金
- National Health and Medical Research Council of Australia [1022707, 1031893, 1035828, 1035955, 0511981, 1002147, 1075451]
- Association Francaise contre les Myopathies [15734, DAJ1891]
- National Hospital Clinical Research Program [A0M10181]
- National Institute of Child Health and Development of the NIH [R01 HD 075802]
- Muscular Dystrophy Association (USA) [MDA201302]
- AUism Charitable Foundation
- National Institute on Aging [AG000114]
- University of Sydney Australian Postgraduate Award
- International Postgraduate Research Scholarship
- University of Western Australia Postgraduate Award
- Dubai-Harvard Foundation for Medical Research postdoctoral fellowship
- Schlumberger Foundation Faculty
- Italian Ministry of Health Ricerca finalizzata [GR-2010-2310981]
- NIH [GM081688, K01 AR062601]
- Muscular Dystrophy Association (USA)
- National Human Genome Research Institute of the NIH [U54 HG003067]
- National Health and Medical Research Council of Australia [1075451] Funding Source: NHMRC
Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of Imod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.
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