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

Abstract

(1) TAF1 reduction in X-linked dystonia-parkinsonism is likely due to the retrotransposon insertion and is recapitulated in induced pluripotent stem cells and differentiated spiny projection neurons. (2) TAF1 reduction is a tractable molecular phenotype of X-linked dystonia-parkinsonism that can be driven by excision of the retrotransposon insertion. (3) Successful rescue of the molecular phenotype in an endogenous, genome-edited model serves as a proof of principle that may successfully be transferred to other inherited neurodegenerative diseases. © 2018 International Parkinson and Movement Disorder Society.

A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism

“…Results of previous studies converge on decreased TAF1 expression, 11,13,21 caused by the SVA insertion, 3,4 as the main disease mechanism driving XDP pathogenesis. Importantly, the reduction of the TAF1 mRNA is a tractable molecular phenotype of XDP that can be rescued by excision of the SVA insertion.…”

“…Generation of iPSCs, iPSC-derived cortical neurons, and MSNs has been conducted as previously described. 4 In addition, blood samples from 31 of our XDP patients were collected in PAXGene tubes (Qiagen, Valencia, CA). From these, RNA was extracted using the manufacturer's protocol.…”

“…1 Finally, the severity of clinical expression differs among patients, causing earlier generalization of dystonia in some and later in others (range = 1-23 years). 1 Recently, 2 independent studies 3,4 demonstrated that the~2,6-kb SINE-VNTR-Alu (SVA) retrotransposon, inserted in intron 32 of TAF1, exhibits a functional effect on TAF1 expression in patient-derived cells. The length of the polymorphic (CCCTCT) n repeat within this SVA insertion inversely correlated with AAO in a cohort of 140 XDP patients.…”

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

“…In an additional experiment, CRISPR/Cas9 excision of the SVA insertion abolished aberrant transcriptional signatures and restored TAF1 expression back to normal, a discovery independently obtained by a similar genome‐editing study conducted by Rakovic and colleagues and published in this issue of Movement Disorders …”

“…In an additional experiment, CRISPR/Cas9 excision of the SVA insertion abolished aberrant transcriptional signatures and restored TAF1 expression back to normal, a discovery independently obtained by a similar genome-editing study conducted by Rakovic and colleagues and published in this issue of Movement Disorders. 5 Both studies strongly suggest that XDP is caused by an SVA retrotransposon insertion, which simplifies the genetic diagnosis of XDP. A targeted therapy could potentially be designed to correct this disease-specific molecular signature using antisense oligonucleotides or small-molecule drugs.…”