MSH3 polymorphisms and protein levels affect CAG repeat instability in Huntington's disease mice.

Area of Science:

• Genetics
• Molecular Biology
• Neurodegenerative Diseases

Background:

• Somatic trinucleotide CAG/CTG repeat expansions contribute to Huntington's disease and myotonic dystrophy progression.
• Variability in repeat instability suggests the presence of genetic modifiers.
• Previous studies show strain-dependent CAG/CTG repeat instability in mice, but underlying genetic modifiers remain unidentified.

Purpose of the Study:

• To identify genetic modifiers of CAG/CTG repeat instability in mouse models.
• To investigate the role of the Msh3 gene in CAG repeat instability.
• To explore the impact of Msh3 protein polymorphisms on repeat stability and disease prognosis.

Main Methods:

• Utilized congenic mouse strains (C57BL/6J and BALB/cByJ) carrying a Huntington's disease (HD) (CAG)∼100 transgene.
• Analyzed repeat instability in liver and striatum tissues.
• Conducted reciprocal congenic crosses to pinpoint the Msh3 gene as the determinant of instability differences.

Main Results:

• The R6/1 HD transgene exhibited expansion-biased repeat mutations in the C57BL/6J background but was stable in the BALB/cByJ background.
• The Msh3 gene was identified as the key determinant, with C57BL/6J Msh3 promoting expansion and BALB/cByJ Msh3 promoting stability.
• Higher expression of the C57BL/6J MSH3 variant correlated with CAG expansions, while low expression of the BALB/cByJ MSH3 variant correlated with CAG stability.

Conclusions:

• Naturally occurring MSH3 protein polymorphisms act as modifiers of CAG repeat instability, likely due to variable protein stability.
• The identified MSH3 polymorphisms significantly impact CAG repeat stability, comparable to Msh2 deficiency.
• Variable CAG instability linked to DNA repair gene polymorphisms, such as MSH3, may have prognostic implications for repeat-associated diseases.