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

Abstract

SummaryX-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease endemic to the Philippines. We integrated genome and transcriptome assembly with induced pluripotent stem cell-based modeling to identify the XDP causal locus and potential pathogenic mechanism.Genome sequencing identified novel variation that was shared by all probands and three recombination events that narrowed the causal locus to a genomic segment including TAF1.Transcriptome assembly in neural derivative cells discovered novel TAF1 transcripts, including a truncated transcript exclusively observed in probands that involved aberrant splicing and intron retention (IR) associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion. This IR correlated with decreased expression of the predominant TAF1 transcript and altered expression of neurodevelopmental genes; both the IR and aberrant TAF1 expression patterns were rescued by CRISPR/Cas9 excision of the SVA. These data suggest a unique genomic cause of XDP and may provide a roadmap for integrative genomic studies in other unsolved Mendelian disorders.

Genome editing in induced pluripotent stem cells rescues TAF1 levels in X‐linked dystonia‐parkinsonism

“…The latter speculation is especially intriguing, given that TAF1 reduction was recapitulated in both iPSCs and SPNs, but statistically significant rescue was only evident in iPSCs in this study. In support of our findings, and while our manuscript was under review, a similar observation using iPSC‐based neuronal models of XDP was published independently . In XDP patient‐derived SPNs, genome editing also resulted in increased TAF1 expression; however, it did not reach significance.…”

An integrated OMICS approach unravels the elusive genetic cause of X‐linked dystonia‐parkinsonism

“…Their efforts resulted in the discovery of a recombination event in a nonmanifesting carrier that likely excludes 2 of the 7 disease‐specific changes from the XDP haplotype, narrowing it at the 3′ end. This finding, combined with the previously reported 5′ border, further reduces the XDP‐linked region at the 3′ end to a minimal linked region of ∼160 kb that contains only 1 gene — TAF1 …”

“…Nevertheless, genetic and expression studies converged on TAF1 as the putative disease‐causing gene in XDP, downregulation of which leads to striatal neurodegeneration . Given this information, Aneichyk and colleagues revisited 2 fundamental questions: (1) Which one among the 7 genetic variants is truly disease‐causing? (2) What is the underlying mechanism by which this variant causes XDP?…”

Estimating contribution of rare non‐coding variants to neuropsychiatric disorders

“…Recent advances in stem cell biology and engineering allow us to analyze accurate (having high construct validity) disease models derived from tissues/cells of mutation carriers . In addition, these genome‐editing and stem cell technologies can be used in combination to newly generate valid disease models, including primate models of neuropsychiatric disorders, and to confirm pathogenicity of an identified non‐coding variant by generating or fixing the mutation …”