Somatic" Cell and Molecular Genetics, VoL 20, No. 1, 1994, pp. 27~8 Structure and Expression of the Huntington's Disease Gene: Evidence against Simple Inactivation Due to an Expanded CAG Repeat Christine M. Ambrose, ~ Mabel P. Duyao, ~ Glenn Barnes, 1 Gillian P. Bates, z Carol S. Lin, ~ Jayalakshmi Srinidhi, ~ Sarah Baxendale, 2 Holger Hummerich, 2 Hans Lehrach, 2 Michael AItherr, 3 John Wasmuth, 3 Alan Buckler, 1 Deanna Church, 1 David Housman, 4 Mary Berks, 5 Gos Micldem, 5 Richard Durbin, 5 Alan Dodge, ~ Andrew Read, 6 James Gusella, ~,7 and Marcy E. MacDonald I 1MolecularNeurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114; 21mperial Cancer Research Fund, Lincoln's Inn Fields, London, U.K.; 3Department of Biological Chemistry, University of California, Irv- me, Califomia 92717; 4Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; 5Sanger Centre, Hinxton Halt, Hinxton, Cambridge, CBIO 1RQ, U.K.; 6Department of Medical Genetics, St. Mary's Hospital, Manchester, U.K.; and 7Depat~ment of Genetics, Harvard Medical School, Boston, Massachusetts 02114 Received 6 December t993 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 toss 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 polyadenyl- ated 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. INTRODUCTION Huntington's disease is a dominant neurodegenerative disorder of mid-life onset in which progressive chorea and dementia result from the premature, specific loss of neurons in the basal ganglia (1). The genetic defect in HD was mapped to chromosome 4 by linkage analysis in 1983 (2). A decade of progressively detailed physical and genetic mapping ensued, producing overlapping cos- mid and yeast artificial chromosome clones sets spanning the HD region in 4p16.3 (3). Using haplotype analysis to focus the search 27 0740-7750/94/0100-0027507.00/0 9 1994 Plenum Publishing Corporation