Structure and expression of the Huntington's disease gene: Evidence against simple inactivation due to an expanded CAG repeat

Abstract

Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expanded, unstable trinucleotide repeat in a novel 4p16.3 gene. To lay the foundation for exploring the pathogenic mechanism in HD, we have determined the structure of the disease gene and examined its expression. The HD locus spans 180 kb and consists of 67 exons ranging in size from 48 bp to 341 bp with an average of 138 bp. Scanning of the HD transcript failed to reveal any additional sequence alterations characteristic of HD chromosomes. A codon loss polymorphism in linkage disequilibrium with the disorder revealed that both normal and HD alleles are represented in the mRNA population in HD heterozygotes, indicating that the defect does not eliminate transcription. The gene is ubiquitously expressed as two alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues, suggesting the operation of interacting factors in determining specificity of cell loss. The HD gene was disrupted in a female carrying a balanced translocation with a breakpoint between exons 40 and 41. The absence of any abnormal phenotype in this individual argues against simple inactivation of the gene as the mechanism by which the expanded trinucleotide repeat causes HD. Taken together, these observations suggest that the dominant HD mutation either confers a new property on the mRNA or, more likely, alters an interaction at the protein level.

RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model

“…Our data show that HD-like symptoms can be improved by partial reduction of mutant htt expression, suggesting that complete elimination of mutant allele expression may not be required. Second, disease allele-specific silencing will require identification and testing of disease-linked polymorphisms, one of which has been identified in exon 58 (43). This proof-of-principle work in the HD-N171-82Q-transgenic model provides evidence that disease allele-specific silencing can be accomplished in vivo.…”

Mechanisms of Toxicity in Huntington’s Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

“…14 Proteinin ilk 17 amino asidi insan, fare, sıçan ve kirpi balığı htt proteinleri ile %100 homoloji gös-termektedir. 17.…”

Using non-coding small RNAs to develop therapies for Huntington's disease

“…[39][40][41][42][43] The typical sequence beginning at this position is 5¢-GAG.GAG.GAG.GAG-3¢; that for D2642 is 5¢-GAG.GAG.GAG-3¢. The deletion of a codon causes the loss of one of the four tandem glutamate residues in the huntingtin protein.…”

“…The three-glutamate species occurs substantially more frequently among HD alleles (38%) than in those without CAG expansion (7%). 39 One skin fibroblast from an HD patient was identified that carried both an HD allele marked by the D2642 deletion and its wild-type counterpart. These cells were transfected with each of four Non-coding small RNAs in developing therapies for HD Y Zhang and RM Friedlander siRNAs designed to target the polymorphic site.…”