RFC1

The protein encoded by this gene is the large subunit of replication factor C, which is a five subunit DNA polymerase accessory protein. Replication factor C is a DNA-dependent ATPase that is required for eukaryotic DNA replication and repair. The protein acts as an activator of DNA polymerases, binds to the 3' end of primers, and promotes coordinated synthesis of both strands. It also may have a role in telomere stability.[6]

RFC1 has been shown to interact with:

• BRD4,[7]
• HDAC1,[8]
• PCNA,[7][9][10][11][12]
• RELA[13] and
• RFC3.[14][15][16]

Biallelic intronic repeat expansions (a series of repeating nucleotide sequences) in the replication factor C subunit 1 (RFC1) gene may be a cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome or CANVAS.[17] Within the poly(A) tail of an AluSx3 element in RFC1, there is eleven repeats of the sequence "AAAAG" which in familial CANVAS becomes "AAGGG" and differs in length from the wild-type sequence. This mutation is also present in a high number of sporadic cases of late-onset ataxia.[17] Mutant biallelic intronic repeat expansions do not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function of this gene.[17]

In patients with the pathogenic RFC1 expansion, sensory neuropathy appears to be a predominant feature and patients may also present with symptoms such as cerebellar dysfunction, vestibular involvement and a dry spasmodic cough therefore, genetic testing is recommended in those with these symptoms.[18]

Due to a diagnostic overlap with CANVAS, researchers have also investigated the presence of RFC1 expansions in pathologically confirmed multiple systems atrophy (MSA) but found a similar alteration frequency (0.7%) to a healthy population, suggesting RFC1 does not have a role in this disease.[19]