Abstract
A higher incidence of diabetes was observed among family members of individuals affected by Huntington’s Disease with no follow-up studies investigating the genetic nature of the observation. Using a genome-wide association study (GWAS), RNA sequencing (RNA-Seq) analysis and western blotting of Rattus norvegicus and human, we were able to identify that the gene family of sortilin receptors was affected in Huntington’s Disease patients. We observed that less than 5% of SNPs were of statistical significance and that sortilins and HLA/MHC gene expression or SNPs were associated with mutant huntingtin (mHTT). These results suggest that ST14A cells derived from R. norvegicus are a reliable model of HD, since sortilins were identified through analysis of the transcriptome in these cells. These findings help highlight the genes involved in mechanisms targeted by diabetes drugs, such as glucose transporters as well as proteins controlling insulin release related to mHTT. To the best of our knowledge, this is the first GWAS using RNA-Seq data from both ST14A rat HD cell model and human Huntington’s Disease.
Highlights
To further access the effect of mutant huntingtin (mHTT) on the biology of sortilins, we investigated single nucleotide polymorphism (SNP) (Figure 2B) and the gene expression (Figure 2C) of sortilins associated with Huntington’s disease (HD)
By interrogating datasets analyzed for transcriptomic regulation and presence of SNPs associated with mHTT in specific genomic regions known to be involved with Type 1 and Type 2 Diabetes, we found that genes from the MHC/HLA locus, regarded as Type 1 Diabetes (T1D) markers [39], were down-regulated in human cells expressing mHTT in the HD iPSC Consortium dataset (HLA-B) (Figure 2C)
We showed that mHTT is associated with increased protein expression of sortilin SORCS1 in ST14A cells (Figure 2A), in agreement with our previous report for mRNA molecules of SORCS1 and that there exists allele association of regions near SORT1, SORL1, SORCS1, SORCS2 and SORCS3 with gene variants in the region of HTT gene in human HD cases (Figure 5)
Summary
Huntington’s disease (HD), a neurodegeneration characterized by motor, cognitive and psychiatric symptoms is caused by an unstable expansion (CAG) in a polyglutamine (polyQ) tract in the N-terminal of the huntingtin (HTT) gene. This condition is triggered when the number of CAG repeats on exon of HTT exceeds 39, while 36-39 CAGs repeats result in an uncertain incidence of the disease [1]. HTT contains HEAT repeats which play an important role in protein-protein interactions. HEAT repeats are a common helical motif in the Huntingtin protein, Elongation Factor 3, protein phosphatase 2A, and TOR1 [3]
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