title: Differential expression of normal and mutant Huntington's disease gene alleles.
abstract: Huntingtin expression was examined by Western blot and immunoprecipitation studies of lymphoblastoid cell lines from Huntington's disease (HD) homozygotes, heterozygotes, and a phenotypically normal individual with a t(4p16.3;12p13.3) breakpoint in the HD gene. The latter produced a reduced level of normal huntingtin without evidence of an altered protein, indicating that simple loss of huntingtin activity does not cause HD. In juvenile onset HD heterozygotes, NH2- and COOH-terminal antisera revealed reduced relative expression from the mutant allele. Pulse-chase studies indicated that huntingtin is a stable protein whose differential allelic expression is not due to destabilization of the mutant isoform. No stable breakdown products specific to mutant huntingtin were detected in either HD homozygotes or heterozygotes. These data are consistent with HD involving either a gain of function or a dominant negative loss of function that operates within severe constraints and suggest that in either case the pathogenic process is usually saturated by the amount of abnormal huntingtin produced from a single mutant allele.
authors.affiliation: Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129, USA.
authors.forename: F
authors.initials: F
authors.lastname: Persichetti
authors.forename: L
authors.initials: L
authors.lastname: Carlee
authors.forename: P W
authors.initials: PW
authors.lastname: Faber
authors.forename: S M
authors.initials: SM
authors.lastname: McNeil
authors.forename: C M
authors.initials: CM
authors.lastname: Ambrose
authors.forename: J
authors.initials: J
authors.lastname: Srinidhi
authors.forename: M
authors.initials: M
authors.lastname: Anderson
authors.forename: G T
authors.initials: GT
authors.lastname: Barnes
authors.forename: J F
authors.initials: JF
authors.lastname: Gusella
authors.forename: M E
authors.initials: ME
authors.lastname: MacDonald
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D015153:Blotting, Western; D002648:Child; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011233:Precipitin Tests; D012016:Reference Values; D014178:Translocation, Genetic
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins