Human Genetics文章：兒童失神性癲癇患者NIPA2基因存在突變
盡管染色體15q11.2區(qū)拷貝數(shù)變異已經(jīng)被確認(rèn)可以引起高加索人群特發(fā)性全身性癲癇(idiopathic generalized epilepsy, IGE)，不過(guò)該區(qū)域存在的癲癇基因尚不清楚。研究中檢測(cè)了中國(guó)兒童失神性癲癇（childhood absence epilepsy，CAE）人群15q11.2區(qū)拷貝數(shù)變異，并檢測(cè)該區(qū)域的選擇性鎂離子轉(zhuǎn)運(yùn)蛋白基因NIPA2的微缺失是否是引起CAE的易感基因。研究者使用Affymetrix SNP5.0芯片檢測(cè)了來(lái)自中國(guó)北方得到198位CAE患者和198個(gè)對(duì)照中的IGE相關(guān)的拷貝數(shù)變異情況，并通過(guò)基于高密度芯片的比較基因組雜交進(jìn)行確認(rèn)。進(jìn)而對(duì)全部380例CAE患者和400例對(duì)照樣品的NIPA2基因編碼區(qū)和外顯子-內(nèi)含子邊界區(qū)域進(jìn)行了測(cè)序。在198個(gè)CAE病人中發(fā)現(xiàn)3例(1.5%)存在15q11.2區(qū)微缺失而在對(duì)照組沒(méi)有檢測(cè)到缺失情況。在380例患者中有3例檢測(cè)到了處于雜合狀態(tài)的NIPA2基因存在點(diǎn)突變或插入/缺失，在700例對(duì)照中則不存在這些突變形式(P=0.043)。這些突變形式包括2種新發(fā)的錯(cuò)義突變(c.532A>T, p.I178F; c.731A>G, p.N244S )，和一種新發(fā)的小片段插入(c.1002_1003insGAT, p.N334_335EinsD )，這些突變形式在400例對(duì)照樣品中均沒(méi)有檢測(cè)到。在本研究第一次鑒定了選擇性鎂離子結(jié)合蛋白基因NIPA2是兒童失神性癲癇的易感基因，確定微缺失是染色體15q11.2區(qū)拷貝數(shù)變異重要的疾病形式，這些突變?cè)谥袊?guó)的疾病人群中具有比已報(bào)道的高加索人群更高的發(fā)生頻率。NIPA2基因的單倍劑量不足可能是15q11.2區(qū)微缺失造成神經(jīng)系統(tǒng)表現(xiàn)的機(jī)制之一。
上述研究中，Affymetrix SNP 5.0芯片服務(wù)在博奧生物有限公司完成。
原文摘要：
NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy
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.