Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia

Mahmoud Fawzi Elsaid, Nader Chalhoub, Tawfeg Ben-Omran, Pankaj Kumar, Hussein Kamel, Khalid Ibrahim, Yasmin Ali Mohamoud, Eman Aldous, Iman Al Azwani, Joel Malek, Karsten Suhre, M. Elizabeth Ross, Alice Kamal Abd El Aleem

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18 Citations (Scopus)


Objective: Exome sequences account for only 2% of the genome and may overlook mutations causing disease. To obtain a more complete view, whole genome sequencing (WGS) was analyzed in a large consanguineous family in which members displayed autosomal recessively inherited cerebellar ataxia manifesting before 2 years of age. Methods: WGS from blood-derived genomic DNA was used for homozygosity mapping and a rare variant search. RNA from isolated blood leukocytes was used for quantitative polymerase chain reaction (PCR), RNA sequencing, and comparison of the transcriptomes of affected and unaffected family members. Results: WGS revealed a point mutation in noncoding RNA RNU12 that was associated with early onset cerebellar ataxia. The U12-dependent minor spliceosome edits 879 known transcripts. Reverse transcriptase PCR demonstrated minor intron retention in all of 9 randomly selected RNAs from this group, and RNAseq showed splicing disruption specific to all U12-type introns detected in blood monocytes from affected individuals. Moreover, 144 minor intron–containing RNAs were differentially expressed, including transcripts for 3 genes previously associated with cerebellar neurodegeneration. Interpretation: Interference with particular spliceosome components, including small nuclear RNAs, cause reproducible uniquely distributed phenotypic and transcript-specific effects, making this an important category of disease-associated mutation. Our approach to differential expression analysis of minor intron–containing genes is applicable to other diseases involving altered transcriptome processing. ANN NEUROL 2017;81:68–78.

Original languageEnglish
Pages (from-to)68-78
Number of pages11
JournalAnnals of Neurology
Issue number1
Publication statusPublished - 1 Jan 2017


ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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