title: An Expanded CAG Repeat in Huntingtin Causes +1 Frameshifting.
abstract: Maintenance of triplet decoding is crucial for the expression of functional protein because deviations either into the -1 or +1 reading frames are often non-functional. We report here that expression of huntingtin (Htt) exon 1 with expanded CAG repeats, implicated in Huntington pathology, undergoes a sporadic +1 frameshift to generate from the CAG repeat a trans-frame AGC repeat-encoded product. This +1 recoding is exclusively detected in pathological Htt variants, i.e. those with expanded repeats with more than 35 consecutive CAG codons. An atypical +1 shift site, UUC C at the 5' end of CAG repeats, which has some resemblance to the influenza A virus shift site, triggers the +1 frameshifting and is enhanced by the increased propensity of the expanded CAG repeats to form a stem-loop structure. The +1 trans-frame-encoded product can directly influence the aggregation of the parental Htt exon 1.
authors.affiliation: From the Institute of Biochemistry, University of Potsdam, 14467 Potsdam, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saffert
authors.affiliation: Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, 20146 Hamburg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Adamla
authors.affiliation: From the Institute of Biochemistry, University of Potsdam, 14467 Potsdam, Germany.
authors.forename: Rico
authors.initials: R
authors.lastname: Schieweck
authors.affiliation: the School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland, and the Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112.
authors.forename: John F
authors.initials: JF
authors.lastname: Atkins
authors.affiliation: From the Institute of Biochemistry, University of Potsdam, 14467 Potsdam, Germany, Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, 20146 Hamburg, Germany, zoya.ignatova@uni-hamburg.de.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Ignatova
mesh_terms: D005091:Exons; D016368:Frameshift Mutation; D006801:Humans; D000071058:Huntingtin Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D019680:Trinucleotide Repeat Expansion
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein
keywords: Huntington disease; aggregation; frameshifting; seeding; translation; translation regulation; trinucleotide repeat disease