Abstract Details

Title Disruption of RNA Processing in Pontocerebellar Hypoplasia with Spinal Muscular Atrophy (PCH1B)

Topic Movement Disorders

Presentation(s) P05 - (-)

Poster/Presentation
Number 047

Objective

Background 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 3'-to-5' RNA processing essential for viability and fidelity of gene expression. The specific contribution of EXOSC3 to exosome function is not known.

Design/Methods 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 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 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.

Authors/Disclosures
PRESENTER	No disclosure on file
Belinda Weller (Biogen)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Giovanni Coppola, MD (UCLA)	Dr. Coppola has received personal compensation for serving as an employee of Regeneron. Dr. Coppola has received stock or an ownership interest from Regeneron.
Joanna C. Jen, MD, PhD (Dept Neurology, Icahn School of Medicine at Mt Sinai)	Dr. Jen has nothing to disclose.

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