A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
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.
Additional Information
Received 26 February 1993, Revised 4 March 1993. We thank the many investigators who have supplied blood samples from HD pedigrees, particularly the Venezuela Huntington's Disease Collaborative Group, and the many investigators who have over the years participated in or contributed to this project. We are also extremely grateful to the HD families themselves for supporting and participating in this research effort. We thank P. M. Conneally, G. Evans, M. Frangione, C. Gilliam, R. Horvitz, L. Moyzis, R. Mulligan, A. Novelletto, A. Tobin, and L. Zipursky for helpful discussions. This work was supported by National Institutes of Health grants NS16367 (Huntington's Disease Center Without Walls), NS22031, and NS25631 and by grants from Bristol-Myers Squibb, Inc., the Hereditary Disease Foundation Collaborative Research Agreement, the Joan and William A. Schreyer/Merrill Lynch Fund to Cure Huntington's Disease of the Hereditary Disease Foundation, the Huntington's Disease Society of America, the Foundation for the Care and Cure of Huntington's Disease, the W. M. Keck Foundation, the William J. Matheson Foundation, the Bay Foundation, The Charles A. Dana Foundation, the Medical Research Council (England), the Welsh Office, and the Wellcome Trust. Fellowship support was provided to C. M. A. by the Andrew B. Cogan Fellowship of the Hereditary Disease Foundation. Other postdoctoral fellowships to various investigators were generously provided by the Hereditary Disease Foundation, the Huntington's Disease Society of America, and the Huntington's Society of Canada. GenBank Accession Number: The accession number for the sequence reported in this paper is L12392.Additional details
- Eprint ID
- 67181
- DOI
- 10.1016/0092-8674(93)90585-E
- Resolver ID
- CaltechAUTHORS:20160519-124048607
- NS16367
- NIH
- NS22031
- NIH
- NS25631
- NIH
- Bristol-Myers Squibb
- Hereditary Disease Foundation
- Huntington's Disease Society of America
- Foundation for the Care and Cure of Huntington's Disease
- W. M. Keck Foundation
- William J. Matheson Foundation
- Bay Foundation
- Charles A. Dana Foundation
- Medical Research Council (UK)
- Welsh Office
- Wellcome Trust
- Huntington's Society of Canada
- Created
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2016-05-19Created from EPrint's datestamp field
- Updated
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2021-11-11Created from EPrint's last_modified field