NR2A and NR2B receptor gene variations modify age at onset in Huntington disease

Abstract

N -Methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity has been proposed to play a role in the pathogenesis of Huntington disease (HD), an autosomal dominantly inherited disorder associated with defined expansions in a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of CAG repeat units is highly predictive for the age at onset (AO) in HD. However, AO is only modestly correlated with repeat length when the HD expansion range is in the high 30s or low 40s. Therefore, we investigated whether the genes for the different subunits composing the multimeric complexes of NMDA receptors (GRIN glutamate receptor, ionotropic, N-methyl-d-aspartate) represent candidates for modulating the AO of HD. In the studied cohort of 167 HD patients, the repeat range from 41 to 45 CAG units accounted for 30.8% of the variance in AO; 12.3% additional variance could be attributed to GRIN2B genotype variation and 4.5% to GRIN2A genotype variation. We conclude that these two genes, coding for NR2B and NR2A subtypes mainly expressed in the striatum, may influence the variability in AO of HD. Neuroprotective strategies for HD patients and persons at risk should be reconsidered in the light of these findings.

Subtype-selective antagonism of N-methyl-d-aspartate receptor ion channels by synthetic conantokin peptides

“…From the latter standpoint, it has been shown that the presence of the NR2A and NR2B subunits, primarily expressed in the striatum, may influence the age of onset of Huntington's chorea (Arning et al, 2005). Another study has suggested a link between the NR2A level and the symptomatic progression of this disease (Ali and Levine, 2006).…”

SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease

“…The relative content of NR2A subunits of NMDA receptors (NMDARs) plays a key role in motor skill performance (25,26) and is genetically associated with HD age of onset (20)(21)(22). Therefore, we tested whether NR2A subunit trafficking and surface expression are altered in symptomatic zQ175 mice.…”

“…symptoms in HD patients (20)(21)(22), and the function of NR2 subunits is also significantly reduced in the striatum from HD brains compared with normal brains, as assessed by glutamate bindings (23,24). Furthermore, NR2A and NR2B subunits play distinct roles in striatum-mediated motor functions.…”

NR1 Receptor Gene Variation is a Modifier of Age at Onset in Turkish Huntington’s Disease Patients

“…This has led to a search for genetic modiiers and environmental factors that inluence the AO. Diverse modiier candidate loci have been suggested to be associated with AO in HD such as GRIN, TP53, hCAD, UCHL1, BDNF, ASK1, and MTHFR [14,17,[23][24][25][26][27][28][29][30][31][32]. However, many reports from diferent research groups have been contradictory.…”

“…There is a signiicant inverse correlation between the AO and the CAG repeat length [11,12]. However, the number of the CAG repeats does not allow an accurate prediction of AO, only 30-70% of the variance in AO can be explained by the repeat size alone [13][14][15][16][17][18][19][20]. The AO varies signiicantly among individuals with the same CAG size, and even monozygotic HD twins may show phenotypic discordance for the disease [21,22].…”