Journal Article

Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia

Tribollet, Eloise, Tomaselli, Pedro J., Versino, Maurizio, Salpietro, Vincenzo, Marques, Wilson J., Buglo, Elena, Züchner, Stephan, Polke, James, Bronstein, Adolfo, Vandrovcova, Jana, Wood, Nick W., Callegari, Ilaria, Kaski, Diego, Cortese, Andrea, Sivakumar, Prasanth, Sullivan, Roisin, Fratta, Pietro, Rossor, Alexander M., Humphrey, Jack, Tariq, Huma, Efthymiou, Stephanie, Houlden, Henry, Andrade, Nadja S., Devigili, Grazia, Rebelo, Adriana, Reilly, Mary M., Simone, Roberto, Jaunmuktane, Zane, Yau, Wai Yan, Ilyas, Muhammad

2019

Overview

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 ( RFC1 ) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG) 11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia. Biallelic expansion of an intronic AAGGG repeat in RFC1 is identified here as a common cause of late-onset ataxia. This expansion occurs in the poly(A) tail of an AluSx3 element and is observed at a carrier frequency of 0.7% in populations of European ancestry.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208 / 692/699/375/346 / 692/699/375/365 / 692/699/375/374 / 692/699/375/430 / Adult / Aged / Agriculture / Alleles / Animal Genetics and Genomics / Ataxia / Ataxia - genetics / Base sequence / Binding sites / Biomedical and Life Sciences / Biomedicine / Brain / Cancer Research / Carrier frequencies / Causes of / Cerebellar ataxia / Cerebellar Ataxia - genetics / Cerebellum / Deoxyribonucleic acid / DNA / DNA damage / DNA sequencing / Europeans / Gene Function / Gene sequencing / Genes / Genetic aspects / Genomes / Genomics / Haplotypes / Human Genetics / Humans / Introns / Introns - genetics / Linkage analysis / Male / Medical schools / Middle Aged / NMR / Nuclear magnetic resonance / Nucleotide sequence / Peripheral neuropathy / Phosphorylation / Polyadenine / Polyadenylation / Proprioception / Repetitive Sequences, Nucleic Acid - genetics / Replication factor C / Replication Protein C - genetics / Siblings / Vestibular system / Whole genome sequencing / Whole Genome Sequencing - methods