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

Naim Panjwani; Michael Wilson; Laura Addis; Jennifer Crosbie; Elaine Wirrell; Stephane Auvin; Roberto Caraballo; Maria Kinali; David McCormick; Caroline Oren; Jacqueline Taylor; John Trounce; Tara Clarke; Cigdem Akman; Steven Kugler; David Mandelbaum; Patricia McGoldrick; Steven Wolf; Paul Arnold; Russell Schachar; Deb Kumar Pal; Lisa Strug

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

Naim Panjwani, Michael Wilson, Laura Addis, Jennifer Crosbie, Elaine Wirrell, Stephane Auvin, Roberto Caraballo, Maria Kinali, David McCormick, Caroline Oren, Jacqueline Taylor, John Trounce, Tara Clarke, Cigdem Akman, Steven Kugler, David Mandelbaum, Patricia McGoldrick, Steven Wolf, Paul Arnold, Russell SchacharDeb Kumar Pal, Lisa Strug

Basic and Clinical Neuroscience

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

Abstract

Objective: Rolandic epilepsy is a common genetic focal epilepsy of childhood, characterized by centrotemporal sharp waves on electroencephalogram. In pre- vious 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 eth- nicity 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 30 untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (3.20–47.22), P = 2.6 9 10ﰁ4 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.

Original language	English
Journal	Annals of Clinical and Translational Neurology
Publication status	Accepted/In press - 2016

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Panjwani, N., Wilson, M., Addis, L., Crosbie, J., Wirrell, E., Auvin, S., Caraballo, R., Kinali, M., McCormick, D., Oren, C., Taylor, J., Trounce, J., Clarke, T., Akman, C., Kugler, S., Mandelbaum, D., McGoldrick, P., Wolf, S., Arnold, P., ... Strug, L. (Accepted/In press). A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy. Annals of Clinical and Translational Neurology.

@article{9a0065f88bca4ecdb23682eb628245fa,

title = "A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy",

abstract = "Objective: Rolandic epilepsy is a common genetic focal epilepsy of childhood, characterized by centrotemporal sharp waves on electroencephalogram. In pre- vious 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 eth- nicity 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 30 untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (3.20–47.22), P = 2.6 9 10ﰁ4 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.",

author = "Naim Panjwani and Michael Wilson and Laura Addis and Jennifer Crosbie and Elaine Wirrell and Stephane Auvin and Roberto Caraballo and Maria Kinali and David McCormick and Caroline Oren and Jacqueline Taylor and John Trounce and Tara Clarke and Cigdem Akman and Steven Kugler and David Mandelbaum and Patricia McGoldrick and Steven Wolf and Paul Arnold and Russell Schachar and Pal, {Deb Kumar} and Lisa Strug",

year = "2016",

language = "English",

journal = "Annals of Clinical and Translational Neurology",

publisher = "John Wiley and Sons Ltd",

}

Panjwani, N, Wilson, M, Addis, L, Crosbie, J, Wirrell, E, Auvin, S, Caraballo, R, Kinali, M, McCormick, D, Oren, C, Taylor, J, Trounce, J, Clarke, T, Akman, C, Kugler, S, Mandelbaum, D, McGoldrick, P, Wolf, S, Arnold, P, Schachar, R, Pal, DK & Strug, L 2016, 'A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy', Annals of Clinical and Translational Neurology.

TY - JOUR

T1 - A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy

AU - Panjwani, Naim

AU - Wilson, Michael

AU - Addis, Laura

AU - Crosbie, Jennifer

AU - Wirrell, Elaine

AU - Auvin, Stephane

AU - Caraballo, Roberto

AU - Kinali, Maria

AU - McCormick, David

AU - Oren, Caroline

AU - Taylor, Jacqueline

AU - Trounce, John

AU - Clarke, Tara

AU - Akman, Cigdem

AU - Kugler, Steven

AU - Mandelbaum, David

AU - McGoldrick, Patricia

AU - Wolf, Steven

AU - Arnold, Paul

AU - Schachar, Russell

AU - Pal, Deb Kumar

AU - Strug, Lisa

PY - 2016

Y1 - 2016

N2 - Objective: Rolandic epilepsy is a common genetic focal epilepsy of childhood, characterized by centrotemporal sharp waves on electroencephalogram. In pre- vious 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 eth- nicity 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 30 untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (3.20–47.22), P = 2.6 9 10ﰁ4 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.

AB - Objective: Rolandic epilepsy is a common genetic focal epilepsy of childhood, characterized by centrotemporal sharp waves on electroencephalogram. In pre- vious 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 eth- nicity 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 30 untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (3.20–47.22), P = 2.6 9 10ﰁ4 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.

M3 - Article

JO - Annals of Clinical and Translational Neurology

JF - Annals of Clinical and Translational Neurology

ER -

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

Abstract

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