Dataset Information

Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10).

ABSTRACT: Spinocerebellar ataxia type 10 (SCA10) is caused by a pentanucleotide repeat expansion of r(AUUCU) within intron 9 of the ATXN10 pre-mRNA. The RNA causes disease by a gain-of-function mechanism in which it inactivates proteins involved in RNA biogenesis. Spectroscopic studies showed that r(AUUCU) repeats form a hairpin structure; however, there were no high-resolution structural models prior to this work. Herein, we report the first crystal structure of model r(AUUCU) repeats refined to 2.8 Å and analysis of the structure via molecular dynamics simulations. The r(AUUCU) tracts adopt an overall A-form geometry in which 3 × 3 nucleotide (5')UCU(3')/(3')UCU(5') internal loops are closed by AU pairs. Helical parameters of the refined structure as well as the corresponding electron density map on the crystallographic model reflect dynamic features of the internal loop. The computational analyses captured dynamic motion of the loop closing pairs, which can form single-stranded conformations with relatively low energies. Overall, the results presented here suggest the possibility for r(AUUCU) repeats to form metastable A-from structures, which can rearrange into single-stranded conformations and attract proteins such as heterogeneous nuclear ribonucleoprotein K (hnRNP K). The information presented here may aid in the rational design of therapeutics targeting this RNA.

SUBMITTER: Park H

PROVIDER: S-EPMC4876817 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10).

Park HaJeung H González Àlex L ÀL Yildirim Ilyas I Tran Tuan T Lohman Jeremy R JR Fang Pengfei P Guo Min M Disney Matthew D MD

Biochemistry 20150612 24

Spinocerebellar ataxia type 10 (SCA10) is caused by a pentanucleotide repeat expansion of r(AUUCU) within intron 9 of the ATXN10 pre-mRNA. The RNA causes disease by a gain-of-function mechanism in which it inactivates proteins involved in RNA biogenesis. Spectroscopic studies showed that r(AUUCU) repeats form a hairpin structure; however, there were no high-resolution structural models prior to this work. Herein, we report the first crystal structure of model r(AUUCU) repeats refined to 2.8 Å an ...[more]

PMID: 26039897

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Project description:Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant cerebellar ataxia caused by nucleotide ATTCT expansion in ATXN10 gene. SCA10 has been reported in patients of cerebellar ataxia from Amerindian/Latin America and in East Asian ancestry. A common founder has been ascribed to the origin of ATTCT repeat expansion mutation in both the population. Here we present our investigation of the SCA10 pentanucleotide repeat expansion in 461 SCA patients of the Indian population. The analysis of multi-ethnic at-risk haplotype C-(ATTCT)n-GGC was performed using genotype data of various ethnic population included in the 1000 Genomes Project (KGP) to infer the prevalence of at-risk haplotype in the Indian populations. Unsurprisingly, none of the patient's DNA samples with (ATTCT)n expansion was observed in pathological range, however, the observed normal range of (ATTCT)n was 8-22 repeats, suggesting very rare or absence of the occurrence of SCA10 in Indian SCA patients. The at-risk haplotype, CGGC was found to be the most prevalent haplotype across different populations and no segregation of CGGC haplotype with large normal or small normal ATTCT repeats length was observed. However, on extended haplotype analysis, some lineage of CGGC with a flanking divergence at 5' end was observed specifically in the American or East Asian population but not in other population in KGP dataset. Together, these evidence points towards the absence of SCA10 in Indian population and haplotype-based analysis also suggests its occurrence to be rare in South Asian, European and African population. Further investigations are required to establish the present finding.SignificanceThe implications of the findings of this study are 1.) For the diagnostic work-up of SCAs in the Indian population and to decide upon inclusion of SCA10 in panel based genetic investigations even for Indians living abroad. 2.) The haplotype based inference of its presumptive prevalence through the estimation of at-risk haplotype using population genetics approach (South-Asians as the background) allowed us to estimate the possible absence of SCA10 in Indian population. SCA10 is a rare autosomal dominant cerebellar ataxia mostly reported among SCA patients from Latin America and recently described in East Asia population. The genetic study of SCA10 performed in the unrelated Indian spinocerebellar ataxia patients with heterogeneous ethnicity confirmed its absence from the Indian population and that conforms to population genetic based inference of its rarity or absence. 3.) This approach may be adopted for the screening of other subtypes of SCAs, i.e. other rare SCAs e.g. SCA31, SCA36, and SCA37.

Dataset Information

Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10).

Publications

Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10).

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