PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats.

Zhenming Yu,Virginia M.-Y Lee,John Q Trojanowski,Nancy M Bonini,Lauren Elman,Alice S Chen-Plotkin,Leo Mccluskey,Yongqing Zhu,Dana Clay-Falcone,Robert G Kalb,Aaron D Gitler,Vivianna M Van Deerlin,Harm Kampinga

doi:10.1371/journal.pone.0017951

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.

Highlights

Amyotrophic lateral sclerosis (ALS, referred to as Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease caused by the degeneration of motor neurons [1,2,3]
We characterized the repeat sequence in 40 of the 45 ALS cases with intermediate length polyQ repeats in the ATXN2 gene of 27–33 in length and nine of the control cases [31]; these constituted a subset of 40 ALS cases we previously reported with expanded ATXN2 alleles for which motor neuron disease was the initial presentation and from which we were able to obtain amplifiable DNA
Multiple faces of ATXN2 in neurological disease PolyQ expansions in ATXN2 are associated with three clinically distinct neurological diseases; these different situations are associated with different repeat lengths and sequence configuration of the DNA repeat region (Figure 3)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS, referred to as Lou Gehrig’s disease) is a progressive, fatal neurodegenerative disease caused by the degeneration of motor neurons [1,2,3]. 10% of ALS cases are familial, with the remainder of cases being sporadic. 12 genetic loci have been identified associated with familial ALS. Mutations in superoxide dismutase 1 (SOD1) account for 15–20% of cases of familial ALS [4]. Transactivate reponse DNA-binding protein (TARDBP, or TDP-43) is a major disease protein of the ubiquitin-positive cytoplasmic inclusions in ALS without SOD1 mutations [5]. Mutations in the TDP43 coding gene TARDBP were later found in multiple cases of familial and sporadic ALS [6,7,8,9], indicating that TDP-43 plays a critical role in disease pathogenesis

Methods

Results

Conclusion