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

Andrea Cortese; Roberto Simone; Roisin Sullivan; Jana Vandrovcova; Huma Tariq; Yau Way Yan; Jack Humphrey; Zane Jaunmuktane; Prasanth Sivakumar; James Polke; Muhammad Ilyas; Eloise Tribollet; Pedro J. Tomaselli; Grazia Devigili; Ilaria Callegari; Maurizio Versino; Vincenzo Salpietro; Stephanie Efthymiou; Diego Kaski; Nick W. Wood; Nadja S. Andrade; Elena Buglo; Adriana Rebelo; Alexander M. Rossor; Adolfo Bronstein; Pietro Fratta; Wilson J. Marques; Stephan Züchner; Mary M. Reilly; Henry Houlden

doi:10.1038/s41588-019-0372-4

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

Andrea Cortese, Roberto Simone, Roisin Sullivan, Jana Vandrovcova, Huma Tariq, Yau Way Yan, Jack Humphrey, Zane Jaunmuktane, Prasanth Sivakumar, James Polke, Muhammad Ilyas, Eloise Tribollet, Pedro J. Tomaselli, Grazia Devigili, Ilaria Callegari, Maurizio Versino, Vincenzo Salpietro, Stephanie Efthymiou, Diego Kaski, Nick W. WoodNadja S. Andrade, Elena Buglo, Adriana Rebelo, Alexander M. Rossor, Adolfo Bronstein, Pietro Fratta, Wilson J. Marques, Stephan Züchner, Mary M. Reilly, Henry Houlden

Research output: Contribution to journal › Article › peer-review

366 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	649-658
Number of pages	10
Journal	Nature Genetics
Volume	51
Issue number	4
DOIs	https://doi.org/10.1038/s41588-019-0372-4
State	Published - 1 Apr 2019
Externally published	Yes

Access to Document

10.1038/s41588-019-0372-4

Cite this

Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yan, Y. W., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., Tomaselli, P. J., Devigili, G., Callegari, I., Versino, M., Salpietro, V., Efthymiou, S., Kaski, D., ... Houlden, H. (2019). Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nature Genetics, 51(4), 649-658. https://doi.org/10.1038/s41588-019-0372-4

@article{16e42a10bdb240888971bc103c06a760,

title = "Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia",

abstract = "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.",

author = "Andrea Cortese and Roberto Simone and Roisin Sullivan and Jana Vandrovcova and Huma Tariq and Yan, {Yau Way} and Jack Humphrey and Zane Jaunmuktane and Prasanth Sivakumar and James Polke and Muhammad Ilyas and Eloise Tribollet and Tomaselli, {Pedro J.} and Grazia Devigili and Ilaria Callegari and Maurizio Versino and Vincenzo Salpietro and Stephanie Efthymiou and Diego Kaski and Wood, {Nick W.} and Andrade, {Nadja S.} and Elena Buglo and Adriana Rebelo and Rossor, {Alexander M.} and Adolfo Bronstein and Pietro Fratta and Marques, {Wilson J.} and Stephan Z{\"u}chner and Reilly, {Mary M.} and Henry Houlden",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = apr,

day = "1",

doi = "10.1038/s41588-019-0372-4",

language = "English",

volume = "51",

pages = "649--658",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "4",

}

Cortese, A, Simone, R, Sullivan, R, Vandrovcova, J, Tariq, H, Yan, YW, Humphrey, J, Jaunmuktane, Z, Sivakumar, P, Polke, J, Ilyas, M, Tribollet, E, Tomaselli, PJ, Devigili, G, Callegari, I, Versino, M, Salpietro, V, Efthymiou, S, Kaski, D, Wood, NW, Andrade, NS, Buglo, E, Rebelo, A, Rossor, AM, Bronstein, A, Fratta, P, Marques, WJ, Züchner, S, Reilly, MM & Houlden, H 2019, 'Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia', Nature Genetics, vol. 51, no. 4, pp. 649-658. https://doi.org/10.1038/s41588-019-0372-4

TY - JOUR

T1 - Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia

AU - Cortese, Andrea

AU - Simone, Roberto

AU - Sullivan, Roisin

AU - Vandrovcova, Jana

AU - Tariq, Huma

AU - Yan, Yau Way

AU - Humphrey, Jack

AU - Jaunmuktane, Zane

AU - Sivakumar, Prasanth

AU - Polke, James

AU - Ilyas, Muhammad

AU - Tribollet, Eloise

AU - Tomaselli, Pedro J.

AU - Devigili, Grazia

AU - Callegari, Ilaria

AU - Versino, Maurizio

AU - Salpietro, Vincenzo

AU - Efthymiou, Stephanie

AU - Kaski, Diego

AU - Wood, Nick W.

AU - Andrade, Nadja S.

AU - Buglo, Elena

AU - Rebelo, Adriana

AU - Rossor, Alexander M.

AU - Bronstein, Adolfo

AU - Fratta, Pietro

AU - Marques, Wilson J.

AU - Züchner, Stephan

AU - Reilly, Mary M.

AU - Houlden, Henry

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85063902267&partnerID=8YFLogxK

U2 - 10.1038/s41588-019-0372-4

DO - 10.1038/s41588-019-0372-4

M3 - Article

C2 - 30926972

AN - SCOPUS:85063902267

SN - 1061-4036

VL - 51

SP - 649

EP - 658

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

Abstract

Access to Document

Fingerprint

Cite this