Journal Article

Early transcriptional changes linked to naturally occurring Huntington's disease mutations in neural derivatives of human embryonic stem cells

Maxime Feyeux, Fany Bourgois-Rocha, Amanda Redfern, Peter Giles, Nathalie Lefort, Sophie Aubert, Caroline Bonnefond, Aurore Bugi, Marta Ruiz, Nicole Deglon, Lesley Jones, Marc Peschanski, Nicholas D. Allen and Anselme L. Perrier

in Human Molecular Genetics

Volume 21, issue 17, pages 3883-3895
Published in print September 2012 | ISSN: 0964-6906
Published online June 2012 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/dds216
Early transcriptional changes linked to naturally occurring Huntington's disease mutations in neural derivatives of human embryonic stem cells

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Huntington's disease (HD) is characterized by a late clinical onset despite ubiquitous expression of the mutant gene at all developmental stages. How mutant huntingtin impacts on signalling pathways in the pre-symptomatic period has remained essentially unexplored in humans due to a lack of appropriate models. Using multiple human embryonic stem cell lines derived from blastocysts diagnosed as carrying the mutant huntingtin gene by pre-implantation genetic diagnosis, we explored early developmental changes in gene expression using differential transcriptomics, combined with gain and loss of function strategies. We demonstrated a down-regulation of the HTT gene itself in HD neural cells and identified three genes, the expression of which differs significantly in HD cells when compared with wild-type controls, namely CHCHD2, TRIM4 and PKIB. Similar dysregulation had been observed previously for CHCDH2 and TRIM4 in blood cells from patients. CHCHD2 is involved in mitochondrial function and PKIB in protein kinase A-dependent pathway regulation, which suggests that these functions may be precociously impacted in HD.

Journal Article.  6992 words.  Illustrated.

Subjects: Genetics and Genomics

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