Researchers have identified a variant in the gene MSH3 that is linked with Huntington’s disease (HD) progression.
The study, “Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study,” was published in the journal The Lancet Neurology.
TRACK-HD was a prospective and observational study which collected data such as imaging, cognitive characteristics, and quantitative motor assessments. This study, which was conducted in patients with early Huntington’s disease, pre-symptomatic Huntington’s disease gene carriers, and control patients, collected data for three years from 2008 to 2011. There were 216 Huntington’s patients enrolled in the study.
Researchers at University College London analyzed data from TRACK-HD to develop a model of disease progression using information gathered on brain imaging and motor and cognitive characteristics of each patient.
Using this model, researchers were able to conduct a genome-wide study which would allow them to identify which particular genetic events were associated with Huntington’s disease progression. Once they discovered specific genetic mutations, they wanted to determine whether their findings would hold true in a different group of Huntington’s patients who were enrolled in the REGISTRY study.
The REGISTRY study, conducted by the European Huntington’s Disease Network, included 1,773 people who were Huntington’s disease mutation carriers. Data was collected over 10 years, from 2003 to 2013.
Once a model for disease progression was constructed by the researchers using data in the TRACK-HD cohort, it was then constructed for the REGISTRY group. Results showed that the TRACK-HD and the REGISTRY models had progression measures that were highly correlated with each other.
Additionally, upon the conduction of genome-wide association analysis, which looked for genetic similarities between the two cohorts of Huntington’s disease patients, they found there was a significant association between three genes on chromosome 5 (MSH3, DHFR and MTRNR2L2) and disease progression in both models.
There was a higher association in TRACK-HD patients than in REGISTRY patients, but findings in both were statistically significant.
In particular, they found there was one single nucleotide polymorphism (variant), which refers to a single change in the gene for MSH3, that caused an amino acid change from a proline to an alanine, and which may end up changing the structure of the protein.
An increased amount of this particular variant was associated with a significant decrease in the rate of change of the Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score and a decrease in the rate of change in UHDRS Total Functional Capacity score.
As these results held true first in the smaller cohort and then in a larger cohort, it indicates that this specific part of chromosome 5 may have a large effect on disease progression. Specifically, the proline to alanine change on amino acid 67 implicates this gene as participating in the progression of Huntington’s disease.
Interestingly, MSH3 has been studied in the context of Huntington’s in animal studies despite this being the first human study to find a link between MSH3 and Huntington’s disease.
MSH3 is expressed in the brain and involved in DNA repair. Huntington’s disease is characterized by repeats of the nucleotides CAG in DNA. In animal HD models, altering levels of Msh3 decreases somatic instability, which prevents further genetic expansion of the CAG repeats that lead to Huntington’s, and also reduces HD-associated phenotypes. Change in the MSH3 gene have also been linked to other diseases, such as myotonic dystrophy type 1.
Data from this study and experimental animal studies indicate that MSH3 could be a potential therapeutic target in Huntington’s disease.