C9orf72 Intermediate Alleles in Patients with Amyotrophic Lateral Sclerosis, Systemic Lupus Erythematosus, and Rheumatoid Arthritis

AbstractThe commonest genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a large hexanucleotide expansion within the non-coding region of theC9orf72 gene. The pathogenic mechanisms of the mutation seem toxic gain of functions, while haploinsufficiency alone appears insufficient to cause neurodegeneration.C9orf72−/− mice rather develop features of autoimmunity. Immune-mediated dysfunctions are involved in the pathogenesis of ALS and FTD and high prevalence of autoimmune disease has recently been observed inC9orf72 expansion-positive patients. Since intermediate repeat expansions result in decreased transcription of the gene, we explored the hypothesis thatC9orf72 intermediate alleles could be a genetic risk for autoimmune conditions. We genotyped 69 systemic lupus erythematosus (SLE) and 77 rheumatoid arthritis (RA) patients, with 68 expansion-negative ALS patients, as control. A cut-off of ≥ 9 and ≤ 30 hexanucleotide units was chosen to define intermediate-length expansions. In the SLE and SLE + RA cohorts, both the number of patients with intermediate expansions and the overall number of intermediate alleles were significantly higher than in controls (23.2% vs. 7.4%,p = 0.020; 13.8% vs. 3.7%,p = 0.006, and 19.9% vs. 7.4%,p = 0.033, 11% vs. 3.7%,p = 0.021, respectively) and discernible although non-significant differences were found for the RA only cohort. Three SLE patients had intermediate-length expansi...
Source: NeuroMolecular Medicine - Category: Neurology Source Type: research