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Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

Increasing evidence links dysregulation of NR2B-containing N-methyl-d-aspartate receptor remodelling and trafficking to Alzheimer’s disease (AD). This theme offers the possibility that the GRIN2B gene, encoding this selective NR2B subunit, represents a potential molecular modulating factor for this disease. Based on this hypothesis, we carried out a mutation scanning of exons and flanking regions of GRIN2B in a well-characterized cohort of AD patients, recruited from Southern Italy. A “de novo” p.K1293R mutation, affecting a highly conserved residue of the protein in the C-terminal domain, was observed for the first time in a woman with familial AD, as the only genetic alteration of relevance. Moreover, an association study between the other detected sequence variants and AD was performed. In particular, the study was focused on five identified single nucleotide polymorphisms: rs7301328, rs1805482, rs3026160, rs1806191 and rs1806201, highlighting a significant contribution from the GRIN2B rs1806201 T allele towards disease susceptibility [adjusted odds ratio (OR) = 1.92, 95% confidence interval (CI) 1.40–2.63, p < 0.001, after correction for sex, age, and APOE ε4 genotype]. This was confirmed by haplotype analysis that identified a specific haplotype, carrying the rs1806201 T allele (CCCTC), over-represented in patients versus controls (adjusted OR = 6.03; p < 0.0001). Although the pathogenic role of the GRIN2B-K1293R mutation in AD is not clear, our data advocate that genetic variability in the GRIN2B gene, involved in synaptic functioning, might provide valuable insights into disease pathogenesis, continuing to attract significant attention in biomedical research on its genetic and functional role.

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Acknowledgments

The authors thank the individuals with AD and their families for making this study possible. This study was partially supported by “Fondazione Carical” (Cosenza, Italy).

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The authors have no conflicts of interest to disclose. Appropriate approval procedures were used concerning human subjects. There was no additional funding.

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Correspondence to Virginia Andreoli.

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702_2013_1125_MOESM1_ESM.tif

Fig. 1 Molecular discovery and characterization of p.K1293R GRIN2B mutation by denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing. The inset shows DHPLC analyses of a control (wild-type pattern with a1-peak trace) and the mutated sample (heterozygous state with three different peaks). Electropherogram of the patient demonstrates a lysine (Lys) to arginine (Arg) substitution at residue 1293

702_2013_1125_MOESM2_ESM.tif

Fig. 2a In silico protein analysis of the same GRIN2B amino acid substitutions by SIFT, PolyPhen, and SNAP programmes. Fig. 2b Evolutionary conservation of lysine 1293. Species, species-specific gene names, protein database accession numbers (www.ncbi.nlm.nih.gov/protein) and partial amino acids sequences are given. Orthologues residues identical to human NR2B K1293 are indicated in bold letters

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Andreoli, V., De Marco, E.V., Trecroci, F. et al. Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease. J Neural Transm 121, 533–542 (2014). https://doi.org/10.1007/s00702-013-1125-7

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