Snapshot: What is RFC1?

RFC1 is a gene that encodes for replication factor C subunit 1, a component of the protein replication factor C (RFC), which plays an important role in DNA synthesis. RFC recruits DNA polymerase, the protein that assembles the building blocks of DNA, to where the DNA needs to be made. RFC is involved in DNA replication, DNA repair, and transcription regulation which controls the expression level of different proteins.

 In 2019, an AAGGG repeat expansion in intron 2 of RFC1 was identified as a cause of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Multiple studies since then have identified the presence of the expansion in clinical ataxia cohorts, ranging from 1% to 30% of the patient population. Genetic studies also suggest that repeat expansions in RFC1 may be the most common genetic cause of ataxia and are likely underdiagnosed. CANVAS was first described as a clinical entity in 2011, and recent studies indicate that symptoms of the diseases caused by repeat expansions in RFC1 can vary from pure cerebellar ataxia to somatosensory impairment and Parkinsonism. The somatosensory system includes the senses of touch, pressure, temperature, pain, and lets us recognize objects and interact with the environment. Parkinsonism is a term that refers to a collection of brain conditions causing slowed movements, stiffness, and tremors. While CANVAS symptoms may vary, they usually present with three key symptoms, which include cerebellar impairment, vestibular hypofunction (condition where the vestibular system in your inner ear, responsible for balance and spatial orientation, is not functioning properly, causing dizziness and instability), and somatosensory loss. RFC1-related symptoms may also present themselves like multiple systems atrophy (MSA), especially the cerebellar type. Multiple System Atrophy Cerebellar type (MSA-C) is a rare, sporadic neurodegenerative disorder that causes difficulties with balance, coordination, and autonomic functions of the body.

Knowledge on how the RFC1 expansion affects the brain is limited. However, postmortem studies from five individuals diagnosed with CANVAS have revealed the loss of Purkinje cells and Bergmann glia in brain tissues. Bergmann glia is a type of astrocyte found within the Purkinje cell layer of the cerebellum. They are structurally and functionally connected to Purkinje cells.

While the mechanisms of RFC1 expansions remain unknown, ongoing research efforts will help to reveal how the expansions lead to disease and will help us identify potential therapeutic targets for safe and effective treatments.

If you would like to learn more about RFC1, take a look at these resources by the National Ataxia Foundation on CANVAS / RFC1 Ataxia.

Written by Asmer Aliyeva and edited by Christina Peng.