RGD Reference Report - Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. - Rat Genome Database

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

Authors: Cortese, Andrea  Simone, Roberto  Sullivan, Roisin  Vandrovcova, Jana  Tariq, Huma  Yau, Wai Yan  Humphrey, Jack  Jaunmuktane, Zane  Sivakumar, Prasanth  Polke, James  Ilyas, Muhammad  Tribollet, Eloise  Tomaselli, Pedro J  Devigili, Grazia  Callegari, Ilaria  Versino, Maurizio  Salpietro, Vincenzo  Efthymiou, Stephanie  Kaski, Diego  Wood, Nick W  Andrade, Nadja S  Buglo, Elena  Rebelo, Adriana  Rossor, Alexander M  Bronstein, Adolfo  Fratta, Pietro  Marques, Wilson J  Züchner, Stephan  Reilly, Mary M  Houlden, Henry 
Citation: Cortese A, etal., Nat Genet. 2019 Apr;51(4):649-658. doi: 10.1038/s41588-019-0372-4. Epub 2019 Mar 29.
RGD ID: 41404727
Pubmed: PMID:30926972   (View Abstract at PubMed)
PMCID: PMC6709527   (View Article at PubMed Central)
DOI: DOI:10.1038/s41588-019-0372-4   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome  IAGP 41404727DNA:repeat:intron: RGD 
Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome  ISORFC1 (Homo sapiens)41404727; 41404727DNA:repeat:intron: RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rfc1  (replication factor C subunit 1)

Genes (Mus musculus)
Rfc1  (replication factor C (activator 1) 1)

Genes (Homo sapiens)
RFC1  (replication factor C subunit 1)


Additional Information