Abstract
While pathogenic copy number variations (CNVs) in 15q11.2 were recently identified in Caucasian patients with idiopathic generalized epilepsies (IGEs), the epilepsy-associated gene(s) in this region is/are still unknown. Our study investigated whether the CNVs in 15q11.2 are associated with childhood absence epilepsy (CAE) in Chinese patients and whether the selective magnesium transporter NIPA2 gene affected by 15q11.2 microdeletions is a susceptive gene for CAE. We assessed IGE-related CNVs by Affymetrix SNP 5.0 microarrays in 198 patients with CAE and 198 controls from northern China, and verified the identified CNVs by high-density oligonucleotide-based CGH microarrays. The coding region and exon–intron boundaries of NIPA2 were sequenced in all 380 patients with CAE and 400 controls. 15q11.2 microdeletions were detected in 3 of 198 (1.5%) patients and in no controls. Furthermore, we identified point mutations or indel in a heterozygous state of the NIPA2 gene in 3 out of 380 patients, whereas they were absent in 700 controls (P = 0.043). These mutations included two novel missense mutations (c.532A>T, p.I178F; c.731A>G, p.N244S) and one small novel insertion (c.1002_1003insGAT, p.N334_335EinsD). No NIPA2 mutation was found in 400 normal controls. We first identified that NIPA2, encoding a selective magnesium transporter, is a susceptible gene of CAE, and 15q11.2 microdeletions are important pathogenic CNVs for CAE with higher frequency in Chinese populations than that previously reported in Caucasians. The haploinsufficiency of NIPA2 may be a mechanism underlying the neurological phenotypes of 15q11.2 microdeletions.
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Acknowledgments
This study was supported by grants from the Ministry of Science and Technology of China (2006AA02A408, 2006CB500701, 2008ZX09312-014, 2011CBA00401). The authors thank Dr. Alexander Merkle and Dr. Yan Dong from Medical school of University of Minnesota, USA and BoldFace Editors, Inc., USA for help with manuscript preparation. We highly appreciate our patients and their families for their participation.
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Y. Jiang, Y. Zhang, and P. Zhang contributed equally to the manuscript.
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Jiang, Y., Zhang, Y., Zhang, P. et al. NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy. Hum Genet 131, 1217–1224 (2012). https://doi.org/10.1007/s00439-012-1149-3
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DOI: https://doi.org/10.1007/s00439-012-1149-3