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Abstract
Objective: The GRIN3B gene encodes NR3B, a motoneuron-specific member of the NMDA type of ionotropic glutamate receptors. NR3B reduces the Ca2+-permeability as well as the overall current of the receptor response and may thereby protect motoneurons against glutamate-mediated excitotoxicity. We tested whether genetic dysfunction of GRIN3B is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS).
Methods: We searched for mutations in the GRIN3B coding region (3.1 kb) in 117 individuals with familial ALS and in 46 individuals with sporadic ALS. We genotyped the newly identified GRIN3B null allele and four “tag single nucleotide polymorphisms (SNPs)” at the GRIN3B locus in 342 individuals with sporadic ALS and in 374 matched controls. The GRIN3B null allele frequency was determined in 2,128 individuals from a worldwide panel of 42 populations. We furthermore compared the GRIN3B coding sequence in primates (human–macaque) and rodents (rat–mouse) to evaluate the molecular evolution of GRIN3B.
Results: Thirty-two SNPs, including 16 previously unreported SNPs, one 27-bp deletion, a polymorphic CAG repeat, and a 4-bp insertion (insCGTT), were identified. Mutational and case–control studies did not reveal variants that cause or modify disease in ALS. Intriguing is an insCGTT variant that truncates the protein at its amino terminus and results in a GRIN3B null allele. We demonstrated a global distribution of the null allele with allele frequencies ranging between 0 and 0.38, and we delineated a null allele specific haplotype of 9.89 kb. Comparative genomic analysis across four taxa demonstrated accelerated evolution of NR3B in primates.
Conclusions: Our study supports the conclusions that 1) GRIN3B does not seem to be associated with familial or sporadic ALS, 2) the GRIN3B null allele is a common polymorphism, 3) the GRIN3B null allele has arisen once and early in human evolution, and 4) the GRIN3B gene belongs to a group of nervous system–related genes that have been subjected to faster evolution during evolution.
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