Intronic pentanucleotide expansion in the replication factor 1 gene ( RFC1 ) is a major cause of adult-onset ataxia

Abstract

The ataxias comprise diseases of both genetic and nongenetic origin with extreme clinical and genetic heterogeneity. They may present as a pure cerebellar form or as part of a more complex neurologic syndrome. Progressive, neurodegenerative sporadic adult-onset ataxias (SAOAs) without a known cause have a prevalence rate of 2.2-12.4 per 100,000. In several ataxia cohorts, repetitive genetic screening using high-coverage ataxia-specific gene panels in combination with next-generation sequencing (NGS) failed to identify a causative gene in 50%-90% of SAOAs.(1-3) Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), first described by Brownstein et al.,(4) is a slowly progressive neurodegenerative disorder with adult onset, affecting the cerebellum, sensory neurons, and the vestibular system. CANVAS is usually sporadic, but occasionally occurs in siblings. Two research groups recently identified large biallelic intronic AAGGG expansions in replication factor C subunit 1 (RFC1) resulting in CANVAS, an adult-onset neurodegenerative ataxia.(5-7)RFC1 normally loads proliferating cell nuclear antigen onto DNA and activates DNA polymerases delta and epsilon to promote the coordinated synthesis of both strands during replication or after DNA damage.(8</SUP)