Analysis of normal C9orf72 repeat length as possible disease modifier in amyotrophic lateral sclerosis

AbstractThe C9orf72 hexanucleotide repeat (HR) expansion is the main genetic cause of amyotrophic lateral sclerosis (ALS), with expansion size from 30 to >4000 units. Normal C9orf72 HR length is polymorphic (2–23 repeats) with alleles >8 units showing a low frequency in the general population. This study aimed to investigate if the normal C9orf72 HR length influences C9orf72 gene expression and acts as disease modifier in ALS patients negative for C9orf72 mutation (ALS-C9Neg). We found that the distribution of HR alleles was similar in 325 ALS-C9Neg and 303 healthy controls. Gene expression analysis in blood revealed a significant increase of total C9orf72 and V3 mRNA levels in ALS-C9Neg carrying two long alleles (L/L; ≥8 units) compared to patients homozygous for the 2-unit short allele (S/S). However, HR allele genotypes (L/L, S/L, S/S) correlated with no clinical parameters. Our data suggest that normal C9orf72 HR length does not act as disease modifier in ALS-C9Neg despite increasing gene expression.Keywords: amyotrophic lateral sclerosisC9orf72gene expressiondisease modifier AcknowledgementsThe Authors acknowledge the ERN Euro-NMD. AR acknowledges “Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics”, Università degli Studi di Milano. VC and SS were recipients of a fellowship from the PhD program in “Experimental Medicine”, Università degli Studi di Milano.Declaration of interestsV.S. is in the Editorial Advisory Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. All the other Authors report no conflicts of interest.Additional informationFundingThis work was supported by Italian Ministry of Health—Ricerca Corrente.