Nature Genetics
4, 387 - 392 (1993)
doi:10.1038/ng0893-387
Trinucleotide repeat length instability and age of onset in Huntington's diseaseM. Duyao1, C. Ambrose1, R. Myers2, A. Novelletto3, F. Persichetti3, M. Frontali4, S. Folstein5, C. Ross6, M. Franz5, M. Abbott6, J. Gray7, P. Conneally7, A. Young8, J. Penney8, Z. Hollingsworth8, I. Shoulson9, A. Lazzarini10, A. Falek11, W. Koroshetz8, D. Sax2, E. Bird12, J. Vonsattel12, E. Bonilla13, J. Alvir14, J. Bickham Conde15, J.-H. Cha16, L. Dure8, F. Gomez17, M. Ramos18, J. Sanchez-Ramos19, S. Snodgrass20, M. de Young14, N. Wexler21, C. Moscowitz21, G. Penchaszadeh21, H. MacFarlane1, M. Anderson1, B. Jenkins1, J. Srinidhi1, G. Barnes1, J. Gusella1, 22
& M. MacDonald1
1Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown Massachusetts 02129, USA
2Department of Neurology, Boston University Medical School, Boston, Massachusetts 02118, USA
3Department of Biology, University of Rome "Tor Vergata", Rome, Italy
4Instituto di Medicina Sperimentale, CNR, Rome, Italy
5Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
6Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
7Department of Medical Genetics, Indiana University Medical Center, Indianapolis, Indiana 46202, USA
8Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Department of Neurology, University of Rochester Medical Center, Rochester, New York 14642, USA
10Department of Neurology, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA
11Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia 30306, USA
12Brain Tissue Resource Center, McLean Hospital and Department of Neuropathology, Harvard Medical School, Belmont, Massachusetts 02178, USA
13Universidad de Zulia, Maracaibo, Venezuela
14Long Island Jewish Hillside Medical Center, Glen Oaks, New York 11004, USA
15Baylor University College of Medicine, Houston, Texas 77009, USA
16Neuroscience Laboratory, Kennedy Kreiger Institute, Baltimore, Maryland 21205, USA
17Aguirre 621-7A, Capital 1414, Buenos Aires, Argentina
18Servicio de Genetica, Hospital Virgen del Camino, 31008 Pamplona, Spain
19Department of Neurology, University of Miami, Miami, Florida 33136, USA
20Pediatric Neurology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
21Departments of Neurology and Psychiatry, College of Physicians and Surgeons, Columbia University, New York 10032 and Hereditary Disease Foundation, 1427 7th St., Suite 2, Santa Monica California 90401, USA
22Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA Correspondence should be addressed to M.M. The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington's disease families. HD chromosomes contained 37−86 repeat units, whereas normal chromosomes displayed 11−34 repeats. The HD repeat length was inversely correlated with the age of onset of the disorder. The HD repeat was unstable in more than 80% of meiotic transmissions showing both increases and decreases in size with the largest increases occurring in paternal transmissions. The targeting of spermatogenesis as a particular source of repeat instability is reflected in the repeat distribution of HD sperm DNA. The analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.
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