title: NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy.
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.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China. drjiangyw@gmail.com
authors.forename: Yuwu
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Pingping
authors.initials: P
authors.lastname: Zhang
authors.forename: Tian
authors.initials: T
authors.lastname: Sang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Taoyun
authors.initials: T
authors.lastname: Ji
authors.forename: Qionghui
authors.initials: Q
authors.lastname: Huang
authors.forename: Han
authors.initials: H
authors.lastname: Xie
authors.forename: Renqian
authors.initials: R
authors.lastname: Du
authors.forename: Bin
authors.initials: B
authors.lastname: Cai
authors.forename: Haijuan
authors.initials: H
authors.lastname: Zhao
authors.forename: Jingmin
authors.initials: J
authors.lastname: Wang
authors.forename: Ye
authors.initials: Y
authors.lastname: Wu
authors.forename: Husheng
authors.initials: H
authors.lastname: Wu
authors.forename: Keming
authors.initials: K
authors.lastname: Xu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.forename: Piu
authors.initials: P
authors.lastname: Chan
authors.forename: Xiru
authors.initials: X
authors.lastname: Wu
mesh_terms: D027682:Cation Transport Proteins; D002648:Child; D002869:Chromosome Aberrations; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D056915:DNA Copy Number Variations; D004832:Epilepsy, Absence / Q000235:genetics*; D005260:Female; D005838:Genotype; D057895:Haploinsufficiency; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: D027682:Cation Transport Proteins; D008565:Membrane Proteins; C478825:NIPA2 protein, human