Mutation and clinical analysis of the CLCC1 gene in amyotrophic lateral sclerosis patients from Central South China

Abstract

IntroductionRecently, chloride channel CLIC‐like 1 (CLCC1) was reported to be a novel ALS‐related gene. We aimed to screen CLCC1 variants in our ALS cohort and further explore the genotype–phenotype correlation of CLCC1‐related ALS.MethodsWe screened rare damaging variants in CLCC1 from our cohorts of 1005 ALS patients and 1224 healthy controls with whole‐exome sequencing in Central South China. Fisher's exact test was conducted for association analysis at the entire gene level and single variant level.ResultsIn total, four heterozygous missense variants in CLCC1 were identified from four unrelated sporadic ALS patients and predicted to be putative pathogenic by in silico tools and protein model prediction, accounting for 0.40% of all patients (4/1005). The four variants were c.A275C (p.Q92P), c.G1139A (p.R380K), c.C1244T (p.T415M), and c.G1328A (p.R443Q), respectively, which had not been reported in ALS patients previously. Three of four variants were located in exon 10. Patients harboring CLCC1 variants seemed to share a group of similar clinical features, including earlier age at onset, rapid progression, spinal onset, and vulnerable cognitive status. Statistically, we did not find CLCC1 to be associated with the risk of ALS at the entire gene level or single variant level.ConclusionOur findings further expanded the genetic and clinical spectrum of CLCC1‐related ALS and provided more genetic evidence for anion channel involvement in the pathogenesis of ALS, but further investigations are needed to verify our findings.

Update on recent advances in amyotrophic lateral sclerosis

“…Another recent study reported different CLCC1 variants, all located at the C-terminus of the protein, which are predicted to affect protein stability and present with a similar ALS phenotype, namely an earlier age at onset with rapid progression and cognitive deficits. Thus, CLCC1 exon 10 might be a potential hotspot for ALS [ 57 ]. Interestingly, a study conducted in 2021 proposed the association of variants in serine palmitoyltransferase, long-chain base subunit 1 ( SPTLC1 ) with juvenile ALS (namely ALS4), but not with adult-onset ALS, and implicated sphingolipid metabolism as a pathway in motor neuron disease [ 58 ].…”