Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Exome sequencing may miss disease-causing mutations outside coding regions.
• Autosomal recessive cerebellar ataxia can manifest in early childhood.

Purpose of the Study:

• To investigate the genetic cause of early-onset cerebellar ataxia in a consanguineous family using whole genome sequencing.
• To explore the role of spliceosome mutations in neurodegenerative diseases.

Main Methods:

• Whole genome sequencing (WGS) for homozygosity mapping and rare variant identification.
• RNA sequencing and quantitative PCR on blood leukocytes to analyze transcriptomes.
• Comparison of gene expression in affected and unaffected family members.

Main Results:

• A point mutation in the noncoding RNA RNU12 was identified as the cause of early-onset cerebellar ataxia.
• The mutation disrupted the U12-dependent minor spliceosome, leading to intron retention in numerous transcripts.
• Differential expression of 144 minor intron-containing RNAs was observed, including genes linked to cerebellar neurodegeneration.

Conclusions:

• Mutations affecting spliceosome components, such as small nuclear RNAs, can lead to specific phenotypic and transcriptomic effects.
• This study demonstrates the importance of considering spliceosome dysfunction in inherited neurodegenerative disorders.
• The analytical approach for differential expression of minor intron-containing genes can be applied to other transcriptome-related diseases.