Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene

Abstract

ObjectiveTo assess the contribution of noncoding repeat expansions in Japanese patients with amyotrophic lateral sclerosis (ALS).MethodsSporadic ALS in Western countries is frequently associated with noncoding repeat expansions in the C9ORF72 gene. Spinocerebellar ataxia type 8 (SCA8) is another noncoding repeat disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Although the involvement of upper and lower motor neurons in SCA8 has been reported, a positive association between SCA8 and ALS remains unestablished. Spinocerebellar ataxia type 36 is a recently identified disease caused by noncoding repeat expansions in the NOP56 gene and is characterized by motor neuron involvement. We collected blood samples from 102 Japanese patients with sporadic ALS and analyzed the ATXN8OS gene by the PCR–Sanger sequencing method and the C9ORF72 and NOP56 genes by repeat-primed PCR assay.ResultsThree patients with ALS (3%) had mutations in the ATXN8OS gene, whereas no patient had a mutation in the C9ORF72 or NOP56 gene. The mutation-positive patients were clinically characterized by neck weakness or bulbar-predominant symptoms. None of our patients had apparent cerebellar atrophy on MRI, but 2 had nonsymptomatic abnormalities in the white matter or putamen.ConclusionsOur finding reveals the importance of noncoding repeat expansions in Japanese patients with ALS and extends the clinical phenotype of SCA8. Three percent seems small but is still relatively large for Japan, considering that the most commonly mutated genes, including the SOD1 and SQSTM1 genes, only account for 2%–3% of sporadic patients each.

Integrative genetic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes

“…SCA3 patients have lower motor neuron loss and have detectable TDP-43 protein inclusions (Seidel et al 2010). Intermediate length expansions, not sufficient to cause ataxia, have been shown to increase ALS risk in several other ataxin family genes, most notably ATXN2 (Elden et al 2010), but also ATXN1 (Tazelaar et al 2020) and ATXN8OS (Hirano et al 2018). The idea of tagging repeat expansions in ATXN3 with common genetic variants has been previously explored in the context of SCA3 (Prudencio et al 2020).…”

“…Common polymorphic short-tandem repeats are a further contributor to genetic risk of ALS, the most prominent being ATXN2, whereby intermediate lengths impart a small increase in ALS risk (Elden et al 2010). Since this finding, other members of the ATXN gene family have been associated with ALS risk (Tazelaar et al 2020;Lattante et al 2018;Hirano et al 2018). The interplay between rare and common genetic variants in shaping ALS risk is still being explored.…”

Prediction of Recurrence in Cervical Cancer Using a Nine-lncRNA Signature

“…Moreover, we also explored the regulatory mechanism of nine-lncRNAs in the signature by searching the published article. Among the nine-lncRNAs, lncRNA ATXN8OS participate in spinocerebellar ataxia by affecting the localization and activity of splicing factors and mutations in the ATXN8OS are associated with the amyotrophic lateral sclerosis (Moseley et al, 2006; Hirano et al, 2018). Dysregulation of lncRNA DIO3OS was closely related with inflammatory bowel disease (Wang et al, 2018).…”

Neutral Lipid Storage Disease Associated with the <b><i>PNPLA2</i></b> Gene: Case Report and Literature Review

“…Total RNA was extracted from muscles of control, the current patient (Pt1), and a previously reported patient (Pt2) with c.576delC (p.Asp192Glufs*64) in exon 5 [6], and reverse-transcribed with oligo dT primer, as described previously [10,11]. The primers set to cover the entire coding sequence were PNPLA2_-168F: 5′-AGGCAGGGCCAGACCCAGCTTCTT-3′ and PNPLA2_1605R: 5′-GACCCCTCTTGGCAACTGTGAG-TC-3′.…”