Dominant Mutation of CCDC78 in a Unique Congenital Myopathy with Prominent Internal Nuclei and Atypical Cores

Majczenko, Karen; Davidson, Ann E.; Camelo-Piragua, Sandra; Agrawal, Pankaj B.; Manfready, Richard A.; Li, Xingli; Joshi, Sucheta M.; Xu, Jishu; Peng, Weiping; Beggs, Alan H.; Li, Jun Z.; Burmeister, Margit; Dowling, James J.

doi:10.1016/j.ajhg.2012.06.012

Cited by 83 publications

(57 citation statements)

References 19 publications

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“…All embryos were manually dechorionated at day 1 after fertilization. Histopathology, including immunofluorescence analysis of isolated myofibers and EM of muscle from whole embryos, was performed as previously described (25,26). this was performed by Complete Genomics and processed through their Standard Pipeline v. 2.2.…”

Section: Lmod3 Mo Zebrafishmentioning

confidence: 99%

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Yuen¹,

Sandaradura²,

Dowling³

et al. 2014

J. Clin. Invest.

164

207

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Nemaline myopathy (NM) is a common form of congenital myopathy, affecting approximately 1 in 50,000 individuals, and is defined by the presence of nonprogressive generalized muscle weakness and numerous electron-dense protein inclusions (nemaline bodies or rods) in skeletal myofibers (1). The most severely affected 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 lmod3 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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Section: Lmod3 Mo Zebrafishmentioning

confidence: 99%

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Yuen¹,

Sandaradura²,

Dowling³

et al. 2014

J. Clin. Invest.

164

207

View full text Add to dashboard Cite

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“…Our group (Dowling) recently identified a dominant splice site mutation in CCDC78 in a family with an unusual congenital myopathy associated with moderate muscle weakness, exercise intolerance, and a combination of cores, protein aggregates, and central nuclei on muscle biopsy [110]. Using a morpholino-based approach, we showed that zebrafish that model the splice site alteration seen in patients exhibit abnormal triad structure and accumulate RyR1 and DHPR aggregates throughout their myofibers.…”

Section: Ccdc78-associated Myopathymentioning

confidence: 99%

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

2014

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The triad is a skeletal muscle substructure responsible for the regulation of excitation-contraction coupling. It is formed by the close apposition of the T-tubule and the terminal sarcoplasmic reticulum. A rapidly growing list of skeletal myopathies, here referred to as triadopathies, are caused by gene mutations in components of the triad. These disorders, at their root, are caused by defects in excitation contraction coupling and intracellular calcium homeostasis. Secondary abnormalities in triad structure and/or function are also reported in several muscle diseases, most notably certain muscular dystrophies. This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field. The emphasis of the review is both on the pathogenesis of triadopathies and their potential treatment.

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“…CNM is due to X-linked recessive mutations in MTM1 encoding myotubularin ["X-linked myotubular myopathy (XLMTM)"] [47], autosomal-dominant mutations in DNM2 encoding dynamin2 [48] and the BIN1 gene encoding amphiphysin 2 [49], autosomal-recessive mutations in BIN1 [50], RYR1 [14], and TTN encoding titin [51], and rarer backgrounds [52][53][54]. Whilst mutations in MTM1 and BIN1 are typically associated with a "pure" CNM picture, histopathological appearance in particular in DNM2-, RYR1-and TTN-related forms is more variable and may also feature cores, CFTD and dystrophic features [14,55,56].…”

Section: Myotubular/centronuclear Myopathy (Mtm/cnm)mentioning

confidence: 99%

Current and future therapeutic approaches to the congenital myopathies

Jungbluth

Ochala

Treves

et al. 2017

Seminars in Cell & Developmental Biology

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a b s t r a c tThe congenital myopathies -including Central Core Disease (CCD), Multi-minicore Disease (MmD), Centronuclear Myopathy (CNM), Nemaline Myopathy (NM) and Congenital Fibre Type Disproportion (CFTD) -are a genetically heterogeneous group of early-onset neuromuscular conditions characterized by distinct histopathological features, and associated with a substantial individual and societal disease burden. Appropriate supportive management has substantially improved patient morbidity and mortality but there is currently no cure. Recent years have seen an exponential increase in the genetic and molecular understanding of these conditions, leading to the identification of underlying defects in proteins involved in calcium homeostasis and excitation-contraction coupling, thick/thin filament assembly and function, redox regulation, membrane trafficking and/or autophagic pathways. Based on these findings, specific therapies are currently being developed, or are already approaching the clinical trial stage. Despite undeniable progress, therapy development faces considerable challenges, considering the rarity and diversity of specific conditions, and the size and complexity of some of the genes and proteins involved.The present review will summarize the key genetic, histopathological and clinical features of specific congenital myopathies, and outline therapies already available or currently being developed in the context of known pathogenic mechanisms. The relevance of newly discovered molecular mechanisms and novel gene editing strategies for future therapy development will be discussed. © 2016 Elsevier Ltd. All rights reserved.

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Dominant Mutation of CCDC78 in a Unique Congenital Myopathy with Prominent Internal Nuclei and Atypical Cores

Cited by 83 publications

References 19 publications

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

Current and future therapeutic approaches to the congenital myopathies

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