2017/07/03 by Peter Holmans, Peter A. Holmans, Thomas H. Massey +1 · 1 citation
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Genetic Neurodegenerative Diseases #Genetics and Neurodevelopmental Disorders #Mitochondrial Function and Pathology
paper · pdf · doi:10.1093/hmg/ddx261
openalex publication_date 2017/07/03 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
In the decades since the genes and mutations associated with the commoner Mendelian disorders were first discovered, technological advances in genetic analysis have made finding genomic variation a much less onerous task. Recently, the global efforts to collect subjects with Mendelian disorders, to better define the disorders and to empower appropriate clinical trials, along with improved genetic technologies, have allowed the identification of genetic variation that does not cause disease, but substantially modifies disease presentation. The advantage of this is it identifies biological pathways and molecules, that, if modified in people, might alter disease presentation. In Huntington's disease (HD), caused by an expanded CAG repeat tract in HTT, genetic variation has been uncovered that is associated with change in the onset or progression of disease. Some of this variation lies in genes that are part of the DNA damage response, previously suggested to be important in modulating expansion of the repeat tract in germline and somatic cells. The genetic evidence implicates a DNA damage response-related pathway in modulating the pathogenicity of the repeat tracts in HD, and possibly, in other trinucleotide repeat disorders. These findings offer new targets for drug development in these currently intractable disorders.