title: Dominant mutation of CCDC78 in a unique congenital myopathy with prominent internal nuclei and atypical cores.
abstract: Congenital myopathies are clinically and genetically heterogeneous diseases that typically present in childhood with hypotonia and weakness and are most commonly defined by changes observed in muscle biopsy. Approximately 40% of congenital myopathies are currently genetically unresolved. We identified a family with dominantly inherited congenital myopathy characterized by distal weakness and biopsy changes that included core-like areas and increased internalized nuclei. To identify the causative genetic abnormality in this family, we performed linkage analysis followed by whole-exome capture and next-generation sequencing. A splice-acceptor variant in previously uncharacterized CCDC78 was detected in affected individuals and absent in unaffected family members and > 10,000 controls. This variant alters RNA-transcript processing and results in a 222 bp in-frame insertion. CCDC78 is expressed in skeletal muscle, enriched in the perinuclear region and the triad, and found in intracellular aggregates in patient muscle. Modeling of the CCDC78 mutation in zebrafish resulted in changes mirroring the human disease that included altered motor function and abnormal muscle ultrastructure. Using a combination of linkage analysis, next-generation sequencing, and modeling in the zebrafish, we have identified a CCDC78 mutation associated with a unique myopathy with prominent internal nuclei and atypical cores.
authors: Molecular & Behavioral Neuroscience Institute, University of Michigan Medical Center, Ann Arbor, MI 48109-2200, USA.
authors: Karen
authors: K
authors: Majczenko
authors: Ann E
authors: AE
authors: Davidson
authors: Sandra
authors: S
authors: Camelo-Piragua
authors: Pankaj B
authors: PB
authors: Agrawal
authors: Richard A
authors: RA
authors: Manfready
authors: Xingli
authors: X
authors: Li
authors: Sucheta
authors: S
authors: Joshi
authors: Jishu
authors: J
authors: Xu
authors: Weiping
authors: W
authors: Peng
authors: Alan H
authors: AH
authors: Beggs
authors: Jun Z
authors: JZ
authors: Li
authors: Margit
authors: M
authors: Burmeister
authors: James J
authors: JJ
authors: Dowling
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D019295:Computational Biology; D005799:Genes, Dominant / Q000235:genetics; D008040:Genetic Linkage; D006801:Humans; D008869:Microtubule-Associated Proteins; D008957:Models, Genetic; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000473:pathology; D016366:Open Reading Frames / Q000235:genetics; D010375:Pedigree; D012326:RNA Splicing / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015027:Zebrafish
chemical_list: C575747:CCDC78 protein, human; D008869:Microtubule-Associated Proteins; D060172:Morpholinos; D009124:Muscle Proteins