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Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

ABSTRACT: X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.

SUBMITTER: Aneichyk T

PROVIDER: S-EPMC5831509 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

Aneichyk Tatsiana T Hendriks William T WT Yadav Rachita R Shin David D Gao Dadi D Vaine Christine A CA Collins Ryan L RL Domingo Aloysius A Currall Benjamin B Stortchevoi Alexei A Multhaupt-Buell Trisha T Penney Ellen B EB Cruz Lilian L Dhakal Jyotsna J Brand Harrison H Hanscom Carrie C Antolik Caroline C Dy Marisela M Ragavendran Ashok A Underwood Jason J Cantsilieris Stuart S Munson Katherine M KM Eichler Evan E EE Acuña Patrick P Go Criscely C Jamora R Dominic G RDG Rosales Raymond L RL Church Deanna M DM Williams Stephen R SR Garcia Sarah S Klein Christine C Müller Ulrich U Wilhelmsen Kirk C KC Timmers H T Marc HTM Sapir Yechiam Y Wainger Brian J BJ Henderson Daniel D Ito Naoto N Weisenfeld Neil N Jaffe David D Sharma Nutan N Breakefield Xandra O XO Ozelius Laurie J LJ Bragg D Cristopher DC Talkowski Michael E ME

Cell 20180201 5

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across mul ...[more]

PMID: 29474918

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Project description:Abstract X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the TAF1 gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dystonia parkinsonism, we focused on the identification of quantitative phenotypic measures that are most strongly associated with disease progression. Our main objective is to establish a comprehensive, quantitative assessment of movement dysfunction and bulbar motor impairments that are sensitive and specific to disease progression in persons with X-linked dystonia parkinsonism. These measures will set the stage for future treatment trials. We enrolled patients with X-linked dystonia parkinsonism and performed a comprehensive oromotor, speech and neurological assessment. Measurements included patient-reported questionnaires regarding daily living activities and both neurologist-rated movement scales and objective quantitative measures of bulbar function and nutritional status. Patients were followed for 18 months from the date of enrollment and evaluated every 6 months during that period. We analysed a total of 87 men: 29 were gene-positive and had symptoms at enrollment, seven were gene-positive and had no symptoms at enrollment and 51 were gene-negative. We identified measures that displayed a significant change over the study. We used principal variables analysis to identify a minimal battery of 21 measures that explains 67.3% of the variance over the course of the study. These measures included patient-reported, clinician-rated and objective quantitative outcomes that may serve as endpoints in future clinical trials. Acuna et al. analysed a total of 87 men: 36 were gene-positive and 51 were gene-negative. We identified a minimal battery of 21 measures that explains 67.3% of the variance over the course of the study and these may serve as endpoints in future clinical trials. See Haq and Brashear (https://doi.org/10.1093/braincomms/fcad125) for a scientific commentary on this article. Graphical Abstract Graphical Abstract

Dataset Information

Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

Publications

Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

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