CCDC78: unveiling the function of a novel gene associated to hereditary myopathy

CCDC78 was indicated about ten years ago as novel candidate gene for the autosomal dominant centronuclear myopathy-4 (CNM4). However, to date, only one family has been described and CCDC78 function remains unclear. Here we deeply analyze for the first time a family harbouring a CCDC78 nonsense mutation. Histopathological features included, as novel histological hallmark, peculiar sarcoplasmic reticulum (SR) abnormalities. We provided evidence of nonsense mediated mRNA decay, defined novel CCDC78 transcripts and, through transcriptome profiling, detected 1035 muscular differentially expressed genes including a series of genes involved in SR. Through coimmunoprecipitation assay and mass spectrometry studies we demonstrated that CCDC78 interacts with two pivotal SR proteins: SERCA1 and CASQ1. We also found an interaction with MYH1, ACTN2 and ACTA1. Our findings shed light on interactors and possible role of CCDC78 in skeletal muscle, thus allowing us to locate the protein in SR and to consider CCDC78 as CNM4 causative gene.