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Ann Clin Transl Neurol. 2016 Jun 2;3(7):512-22. doi: 10.1002/acn3.320. eCollection 2016 Jul.

A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy.

Author information

1
Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada.
2
Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Department of Molecular Genetics University of Toronto Toronto Ontario M5S 1A1 Canada.
3
Department of Basic and Clinical Neuroscience Institute of Psychiatry, Psychology and Neuroscience King's College London London SE5 9RX United Kingdom; Neuroscience Discovery Research Eli Lilly and Company Erl Wood, Surrey GU20 6PH United Kingdom.
4
Neurosciences and Mental Health Program Research Institute The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Department of Psychiatry The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada.
5
Division of Child and Adolescent Neurology Mayo Clinic Rochester Minnesota 55905.
6
Service de neurologie pédiatrique/Inserm 1141 Hôpital Robert Debré AP-HP, 48 boulevard Sérurier Paris 75019 France.
7
Department of Neurology Hospital de Pediatría "Prof Dr Juan P Garrahan" Combate de los Pozos 1881 C1245AAM Buenos Aires Argentina.
8
Chelsea and Westminster Hospital London SW10 9NH United Kingdom.
9
King's College Hospital London SE5 9RS United Kingdom.
10
Northwick Park Hospital Middlesex HA1 3UJ United Kingdom.
11
Barnet and Chase Farm Hospitals Enfield, Greater London EN2 8JL United Kingdom.
12
Brighton and Sussex University Hospitals Brighton BN1 6AG United Kingdom.
13
Department of Epidemiology Columbia University New York New York 10027.
14
Neurological Institute Columbia University Medical Centre New York, New York 10032.
15
Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine Philadelphia Pennsylvania 19104.
16
Hasbro Children's Hospital and the Warren Alpert Medical School of Brown University Providence Rhode Island 02903.
17
Beth Israel Medical Center New York, New York 10003.
18
Neurosciences and Mental Health Program Research Institute The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Department of Psychiatry The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Mathison Centre for Mental Health Research and Education University of Calgary Calgary Alberta T2N 4Z6 Canada.
19
Department of Basic and Clinical Neuroscience Institute of Psychiatry, Psychology and Neuroscience King's College London London SE5 9RX United Kingdom; King's College Hospital London SE5 9RS United Kingdom; Evelina London Children's Hospita lLondon SE1 7EH United Kingdom.
20
Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Division of Biostatistics Dalla Lana School of Public Health University of Toronto Toronto Ontario M5T 3M7 Canada; The Centre for Applied Genomics The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada.

Abstract

OBJECTIVE:

Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome-wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4-PAX6 locus in two independent US and Canadian case-control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array.

METHODS:

We fine-mapped the ELP4-PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome-12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance.

RESULTS:

Homozygosity at the T allele of SNP rs662702 in the 3' untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20-47.22), P = 2.6 × 10(-4) and is seen in 3.9% of cases but only 0.3% of controls.

INTERPRETATION:

The minor T allele of SNP rs662702 disrupts regulation by microRNA-328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.

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