A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes

ME MacDonald, CM Ambrose, MP Duyao, RH Myers… - Cell, 1993 - cell.com
ME MacDonald, CM Ambrose, MP Duyao, RH Myers, C Lin, L Srinidhi, G Barnes, SA Taylor…
Cell, 1993cell.com
The Huntington's disease (HD) gene has been mapped in 4p16. 3 but has eluded
identification. We have used haplotype analysis of linkage disequilibrium to spotlight a small
segment of 4p16. 3 as the likely location of the defect. A new gene, 1715, isolated using
cloned trapped exons from the target area contains a polymorphic trinucleotide repeat that is
expanded and unstable on HD chromosomes. A (CAG) n repeat longer than the normal
range was observed on HD chromosomes from all 75 disease families examined …
Abstract
The Huntington's disease (HD) gene has been mapped in 4p16.3 but has eluded identification. We have used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect. A new gene, 1715, isolated using cloned trapped exons from the target area contains a polymorphic trinucleotide repeat that is expanded and unstable on HD chromosomes. A (CAG)n repeat longer than the normal range was observed on HD chromosomes from all 75 disease families examined, comprising a variety of ethnic backgrounds and 4p 16.3 haplotypes. The (CAG)n repeat appears to be located within the coding sequence of a predicted ≈348 kd protein that is widely expressed but unrelated to any known gene. Thus, the HD mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
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