RNA exosomes are multi-subunit complexes conserved throughout evolution1 and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability2. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596)3,4,5,6. We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.
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The authors are grateful for the generosity of the families who participated in this study. The sequencing and analytical work were supported by the Bioinformatics and Genomics Core of the UCLA Muscular Dystrophy Core Center (US National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) P30AR057230) within the Center for Duchenne Muscular Dystrophy. We appreciate fibroblasts from three subjects from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) Brain and Tissue Bank for Developmental Disorders. We acknowledge the contribution of clinical data by P. Carpenter (University of California, Irvine). The work was supported by the NIH/National Eye Institute (NEI) (R01 EY015311 and NINDS R01 NS064183 to J.C.J.), Deutsche Forschungsgemeinschaft (Ru-746/1-1 to S.R.-S. and K.Z.), IZKF Aachen (N5-4 to S.R.-S. and J.S.), the Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence (M.M.R.), the Internal Grant Agency of the Ministry of Health of the Czech Republic (NS 10552-3 to P.S.) and Xunta de Galicia–Plan Galego de InvestigaCión, Desenvolvemento e Innovación Tecnolóxica (INCITE) (10PXIB9101280PR to M.-J.S.).
The authors declare no competing financial interests.
Supplementary Note, Supplementary Tables 1–5 and Supplementary Figures 1–4 (PDF 942 kb)
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