Mutant huntingtin messenger RNA containing single nucleotide polymorphism rs362331 (mHTT mRNA (rs362331))

Mutant huntingtin messenger RNA containing single nucleotide polymorphism (SNP) rs362331 is a specific molecular target used in the development of allele-selective therapies for Huntington's disease (HD). HD is a fatal neurodegenerative condition caused by a CAG trinucleotide repeat expansion in the HTT gene, which leads to the production of a toxic mutant huntingtin (mHTT) protein (MacDonald et al., 1993, Cell). Because the wild-type huntingtin (wtHTT) protein plays essential roles in neuronal health and development, non-selective silencing of both alleles may carry safety risks. The rs362331 SNP is a genetic variation frequently found on the same chromosome as the CAG expansion (in linkage disequilibrium), allowing it to serve as a unique marker for the mutant transcript (Southwell et al., 2014, Molecular Therapy). Therapeutic agents, such as antisense oligonucleotides (ASOs) like WVE-120101, are designed to bind specifically to the mRNA sequence containing the rs362331 variant, triggering its degradation while leaving the wild-type mRNA intact (Wave Life Sciences, 2021). This precision medicine approach aims to reduce the levels of toxic mHTT protein in the central nervous system, thereby addressing the underlying cause of the disease while maintaining the protective functions of the wild-type protein.

Other names

HTT mRNA rs362331mHTT mRNA rs362331Mutant HTT transcript rs362331rs362331-targeted huntingtin mRNA

Allele-specific knockdown via RNase H-mediated mRNA degradation