|Title||Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Elsaid MFawzi, Chalhoub N, Ben-Omran T, Kumar P, Kamel H, Ibrahim K, Mohamoud Y, Al-Dous E, Al-Azwani I, Malek JA, Suhre K, M Ross E, Aleem AAbdel|
|Date Published||2017 Jan|
|Keywords||Adolescent, Adult, Child, Female, Genetic Predisposition to Disease, Humans, Male, Point Mutation, Polymorphism, Single Nucleotide, RNA, Small Nuclear, RNA, Untranslated, Sequence Analysis, RNA, Spinocerebellar Degenerations, Young Adult|
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.
|Alternate Journal||Ann. Neurol.|