Disruption of RNA Processing in Pontocerebellar Hypoplasia with Spinal Muscular Atrophy (PCH1B) (P05.047)

OBJECTIVE: To test the hypothesis that PCH1-causing mutations in EXOSC3 disrupts normal exosome function in RNA processing and turnover. BACKGROUND: RNA dysregulation is emerging as an important etiology of neurodegeneration in a broad range of neurological disorders including spinal muscular atrophy, amyotrophic lateral sclerosis, and spinocerebellar ataxia type 36 that affect motor neurons and cerebellar neurons. Pervasive genomewide transcription further underscores the importance of the regulation of RNA metabolism. We recently discovered recessive mutations in a gene EXOSC3 causing pontocerebellar hypoplasia type 1B (PCH1B, OMIM614678), characterized by infantile cerebellar hypoplasia, spinal muscular atrophy, progressive microcephaly, and profound global developmental delay. EXOSC3 encodes a core component of the RNA exosomes (distinct from exosome vesicles), which are multi-subunit complexes conserved throughout evolution that are the major cellular machinery for 39-to-59 RNA processing essential for viability and fidelity of gene expression. The specific contribution of EXOSC3 to exosome function is not known. DESIGN/METHODS: RNA sequencing using an Illumina HiSeq2000 sequencer was performed on libraries generated from total RNA extracted from peripheral blood from affected individuals in our index family and their parents who are carriers along with unaffected siblings to characterize EXOSC3 mutation-related alterations in the transcriptomes. RESULTS: RNA-seq data from the affecteds compared to mutation carriers and normal controls from our index family demonstrated differential gene expression, changes in non-coding RNAs, and disruption of RNA processing, which correlated with the disease status. CONCLUSIONS: These findings strongly implicate dysregulation of RNA processing as a direct consequence of PCH1-causing EXOSC3 mutations. Ongoing studies may 1) clarify the contribution of the non-enzymatic core component EXOSC3 to the function of exosome, and 2) elucidate how dysregulation in RNA processing may lead to PCH1B, with potentially shared cellular pathways in other motor and cerebellar neurodevelopmental and neurodegenerative disorders involving RNA processing. Supported by: In part by NIH/NEI R01 EY015311 and NINDS R01 NS064183. We thank the UCLA Informatics Center for Neurogenetics and Neurogenomics (ICNN, NINDS P30NS062691) which supports the provision of bioinformatics services (statistical genetics, sequence analysis, and gene expression analysis) to UCLA neuroscientists. Disclosure: Dr. Wan has nothing to disclose. Dr. Mamsa has nothing to disclose. Dr. Blum has nothing to disclose. Dr. Sears has nothing to disclose. Dr. Coppola has nothing to disclose. Dr. Jen has received personal compensation in an editorial capacity for Experimental Brain Research.