Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat.
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.
Ambrose
Christine M
CM
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
Duyao
Mabel P
MP
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
Barnes
Glenn
G
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
Bates
Gillian P
GP
Imperial Cancer Research Fund. Lincoln's Inn Fields, London UK
Lin
Carol S
CS
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
Srinidhi
Jayalakshmi
J
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
Baxendale
Sarah
S
Imperial Cancer Research Fund. Lincoln's Inn Fields, London UK
Hummerich
Holger
H
Imperial Cancer Research Fund. Lincoln's Inn Fields, London UK
Lehrach
Hans
H
Imperial Cancer Research Fund. Lincoln's Inn Fields, London UK
Altherr
Michael
M
Department of Biological Chemistry, University of California, Irvine
Wasmuth
John
J
Department of Biological Chemistry, University of California, Irvine
Buckler
Alan
A
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
Church
Deanna
D
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
Housman
David
D
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge
Berks
Mary
M
Sanger Centre, Cambridge, UK
Micklem
Gos
G
Sanger Centre, Cambridge, UK
Durbin
Richard
R
Sanger Centre, Cambridge, UK
Dodge
Alan
A
Department of Medical Genetics, St. Mary's Hospital, Manchester, UK
Read
Andrew
A
Department of Medical Genetics, St. Mary's Hospital, Manchester, UK
Gusella
James
J
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.|Department of Genetics, Harvard Medical School, Boston
MacDonald
Marcy E
ME
Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston 02114.
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
D003062:Codon; D018076:DNA, Complementary; D012333:RNA, Messenger