Article type: Research Article
Authors: Liu, Wanzhao | Chaurette, Joanna | Pfister, Edith L. | Kennington, Lori A. | Chase, Kathryn O. | Bullock, Jocelyn | Vonsattel, Jean Paul G. | Faull, Richard L.M. | Macdonald, Douglas | DiFiglia, Marian | Zamore, Phillip D. | Aronin, Neil
Affiliations: RNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA | Department of Anatomy with Radiology, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand | New York Brain Bank, Neuropathology Core, Alzheimer Disease Research Center Taub Institute, Columbia University, New York, NY, USA | CHDI Foundation Inc., Los Angeles, CA, USA | MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA | RNA Therapeutics Institute, Department of Biochemistry and Molecular Pharmacology, and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA, USA
Note: [] Correspondence to: Neil Aronin, RNA Therapeutics Institute and Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Tel.: +1 508 856 6559; Fax: +1 508 856 6696; E-mail: [email protected]
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). Conclusion: 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.
Keywords: Huntington's disease, mRNA, HTT mRNA alleles, Huntington's disease neuropathology grade
DOI: 10.3233/JHD-130079
Journal: Journal of Huntington's Disease, vol. 2, no. 4, pp. 491-500, 2013
