RFC1

Replication factor C subunit 1 is a protein that in humans is encoded by the RFC1 gene.^[5][6]

Function

The protein encoded by this gene is the large subunit of

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

Clinical relevance

Biallelic intronic repeat expansions (a series of repeating nucleotide sequences) in the replication factor C subunit 1 (RFC1) gene causes cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS).^[17] Within the poly(A) tail of an AluSx3 element in RFC1, there are eleven repeats of the pentanucleotide "AAAAG". Repeat expansion and polymorphic configuration are observed in part of the population, with increased number of repeats associated to alternative "AAAGG", "AAGGG" and "ACAGG" pentanucleotides.^[18] In particular, biallelic "AAGGG" and "ACAGG" repeat expansion have disproportionately been observed in patients with CANVAS. Biallelic "AAGGG" repeat expansion is also reported in a high number of sporadic cases of late-onset ataxia,^[17] isolate sensory neuropathy^[19][20] and, less frequently, isolate cerebellar ataxia.^[21] Due to a diagnostic overlap with CANVAS, researchers have also investigated the presence of RFC1 expansions in pathologically confirmed multiple system atrophy (MSA) but found a similar alteration frequency (0.7%) to a healthy population, suggesting RFC1 does not have a role in this disease.^[22]

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.^[23]

References