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.

The absence of NIPA2 enhances neural excitability through BK (big potassium) channels

“…NIPA2 mutations have been observed in children with CAE, resulting in decreased intracellular magnesium concentrations . However, whether changes in NIPA2 function enhance neuronal excitability remains unknown.…”

“…NIPA family members are nonselective magnesium transporters except NIPA2 , which is highly selective to the extracellular‐to‐intracellular transfer of magnesium . NIPA2 mutations associated with CAE have also been reported, at least in the Han Chinese population . A previous study illustrated that loss‐of‐function NIPA2 mutations may cause the accumulation of NIPA2 proteins in the endoplasmic reticulum, block magnesium transport, and affect neuronal excitability …”

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

“…This CNV encompasses four non-imprinted genes (figure 3): NIPA1 , NIPA2 , CYFIP1 and TUBGCP5 36 38. Three of them are implicated in CNS development and/or function: NIPA1 and NIPA2 are widely expressed in neuronal tissues and CNS and mediate magnesium (Mg 2+ ) transport;68 69 when mutated, they cause autosomal dominant hereditary spastic paraplegia70 and childhood absence epilepsy,71 respectively. CYFIP1 is expressed in the brain and encodes a protein that interacts with fragile X mental retardation protein (FMRP), the protein product of the fragile X syndrome gene 72.…”

Genetic and epigenetic mechanisms of epilepsy: a review

“…The 15q11.2 microdeletion disrupted non-imprinted genes in Prader–Willi syndrome (PWS)/Angelman syndrome (AS) 2 ( NIPA2 ) in patients with CAE58 and schizophrenia59 in two independent studies in the Han Chinese populations. This region contained four highly conserved and non-imprinted genes, NIPA1 , NIPA2 , CYFIP1 , and TUBGCP5 .…”