title: Increased Steady-State Mutant Huntingtin mRNA in Huntington's Disease Brain.
abstract: BACKGROUND
  Huntington's disease is caused by expansion of CAG trinucleotide repeats in the first exon of the huntingtin gene, which is essential for both development and neurogenesis. Huntington's disease is autosomal dominant. The normal allele contains 6 to 35 CAG triplets (average, 18) and the mutant, disease-causing allele contains >36 CAG triplets (average, 42).
  
  
  OBJECTIVE
  We examined 279 postmortem brain samples, including 148 HD and 131 non-HD controls. A total of 108 samples from 87 HD patients that are heterozygous at SNP rs362307, with a normal allele (18 to 27 CAG repeats) and a mutant allele (39 to 73 CAG repeats) were used to measure relative abundance of mutant and wild-type huntingtin mRNA.
  
  
  METHODS
  We used allele-specific, quantitative RT-PCR based on SNP heterozygosity to estimate the relative amount of mutant versus normal huntingtin mRNA in postmortem brain samples from patients with Huntington's disease.
  
  
  RESULTS
  In the cortex and striatum, the amount of mRNA from the mutant allele exceeds that from the normal allele in 75% of patients. In the cerebellum, no significant difference between the two alleles was evident. Brain tissues from non-HD controls show no significant difference between two alleles of huntingtin mRNAs. Allelic differences were more pronounced at early neuropathological grades (grades 1 and 2) than at late grades (grades 3 and 4).
  
  
  CONCLUSIONS
  More mutant HTT than normal could arise from increased transcription of mutant HTT allele, or decreased clearance of mutant HTT mRNA, or both. An implication is that equimolar silencing of both alleles would increase the mutant HTT to normal HTT ratio.
authors: RNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Wanzhao
authors: W
authors: Liu
authors: RNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Joanna
authors: J
authors: Chaurette
authors: RNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Edith L
authors: EL
authors: Pfister
authors: RNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Lori A
authors: LA
authors: Kennington
authors: RNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Kathryn O
authors: KO
authors: Chase
authors: Department of Anatomy with Radiology, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors: Jocelyn
authors: J
authors: Bullock
authors: New York Brain Bank, Neuropathology Core, Alzheimer Disease Research Center Taub Institute, Columbia University, New York, NY, USA.
authors: Jean Paul G
authors: JP
authors: Vonsattel
authors: Department of Anatomy with Radiology, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors: Richard L M
authors: RL
authors: Faull
authors: CHDI Foundation Inc., Los Angeles, CA, USA.
authors: Douglas
authors: D
authors: Macdonald
authors: MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Marian
authors: M
authors: DiFiglia
authors: RNA Therapeutics Institute, Department of Biochemistry and Molecular Pharmacology, and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Phillip D
authors: PD
authors: Zamore
authors: RNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Neil
authors: N
authors: Aronin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance; D001921:Brain / Q000378:metabolism*; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger
keywords: HTT mRNA alleles; Huntington's disease; Huntington's disease neuropathology grade; mRNA