title: 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.
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Ambrose
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: Mabel P
authors.initials: MP
authors.lastname: Duyao
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: Glenn
authors.initials: G
authors.lastname: Barnes
authors.affiliation: Imperial Cancer Research Fund. Lincoln's Inn Fields, London UK
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: Carol S
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Srinidhi
authors.affiliation: Imperial Cancer Research Fund. Lincoln's Inn Fields, London UK
authors.forename: Sarah
authors.initials: S
authors.lastname: Baxendale
authors.affiliation: Imperial Cancer Research Fund. Lincoln's Inn Fields, London UK
authors.forename: Holger
authors.initials: H
authors.lastname: Hummerich
authors.affiliation: Imperial Cancer Research Fund. Lincoln's Inn Fields, London UK
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Department of Biological Chemistry, University of California, Irvine
authors.forename: Michael
authors.initials: M
authors.lastname: Altherr
authors.affiliation: Department of Biological Chemistry, University of California, Irvine
authors.forename: John
authors.initials: J
authors.lastname: Wasmuth
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: Alan
authors.initials: A
authors.lastname: Buckler
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: Deanna
authors.initials: D
authors.lastname: Church
authors.affiliation: Center for Cancer Research, Massachusetts Institute of Technology, Cambridge
authors.forename: David
authors.initials: D
authors.lastname: Housman
authors.affiliation: Sanger Centre, Cambridge, UK
authors.forename: Mary
authors.initials: M
authors.lastname: Berks
authors.affiliation: Sanger Centre, Cambridge, UK
authors.forename: Gos
authors.initials: G
authors.lastname: Micklem
authors.affiliation: Sanger Centre, Cambridge, UK
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: Department of Medical Genetics, St. Mary's Hospital, Manchester, UK
authors.forename: Alan
authors.initials: A
authors.lastname: Dodge
authors.affiliation: Department of Medical Genetics, St. Mary's Hospital, Manchester, UK
authors.forename: Andrew
authors.initials: A
authors.lastname: Read
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.|Department of Genetics, Harvard Medical School, Boston
authors.forename: James
authors.initials: J
authors.lastname: Gusella
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D002460:Cell Line; D003062:Codon; D018076:DNA, Complementary; D005091:Exons; D005260:Female; D005315:Fetal Diseases / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D006816:Huntington Disease / Q000196:embryology / Q000235:genetics*; D007438:Introns; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D014178:Translocation, Genetic
chemical_list: D003062:Codon; D018076:DNA, Complementary; D012333:RNA, Messenger