title: PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive disease leading to paralysis and death. Recently, intermediate length polyglutamine (polyQ) repeats of 27-33 in ATAXIN-2 (ATXN2), encoding the ATXN2 protein, were found to increase risk for ALS. In ATXN2, polyQ expansions of ≥ 34, which are pure CAG repeat expansions, cause spinocerebellar ataxia type 2. However, similar length expansions that are interrupted with other codons, can present atypically with parkinsonism, suggesting that configuration of the repeat sequence plays an important role in disease manifestation in ATXN2 polyQ expansion diseases. Here we determined whether the expansions in ATXN2 associated with ALS were pure or interrupted CAG repeats, and defined single nucleotide polymorphisms (SNPs) rs695871 and rs695872 in exon 1 of the gene, to assess haplotype association. We found that the expanded repeat alleles of 40 ALS patients and 9 long-repeat length controls were all interrupted, bearing 1-3 CAA codons within the CAG repeat. 21/21 expanded ALS chromosomes with 3CAA interruptions arose from one haplotype (GT), while 18/19 expanded ALS chromosomes with <3CAA interruptions arose from a different haplotype (CC). Moreover, age of disease onset was significantly earlier in patients bearing 3 interruptions vs fewer, and was distinct between haplotypes. These results indicate that CAG repeat expansions in ATXN2 associated with ALS are uniformly interrupted repeats and that the nature of the repeat sequence and haplotype, as well as length of polyQ repeat, may play a role in the neurological effect conferred by expansions in ATXN2.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Yu
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhu
authors.forename: Alice S
authors.initials: AS
authors.lastname: Chen-Plotkin
authors.forename: Dana
authors.initials: D
authors.lastname: Clay-Falcone
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kalb
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D000067528:Ataxins; D001483:Base Sequence; D016022:Case-Control Studies; D003062:Codon / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010455:Peptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D000067528:Ataxins; D003062:Codon; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine