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This Article Figures Only Full Text Full Text (PDF) Data Supplement All Versions of this Article: 01.wnl.0000271078.51280.17v1 01.wnl.0000271078.51280.17v2 70/9/666    most recent Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Niemann, S. Articles by Hayashi, Y. PubMed PubMed Citation Articles by Niemann, S. Articles by Hayashi, Y. Related Collections All Neuromuscular Disease Anterior nerve cell disease Amyotrophic lateral sclerosis Case control studies All Genetics Association studies in genetics

Motoneuron-specific NR3B gene

No association with ALS and evidence for a common null allele

From the RIKEN-MIT Neuroscience Research Center, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA (S.N., M.J.C., Y.H.); Cecil B. Day Laboratory for Neuromuscular Research and Department of Neurology, Harvard Medical School, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA (S.N., J.E.L., B.H., P.S., R.H.B.); Department of Genetics, Yale University School of Medicine, New Haven, CT (W.C.S., K.K.K.); and Howard Hughes Medical Institute, Department of Human Genetics, University of Chicago, Chicago, IL (B.T.L.). S.N. is currently with Epigenomics AG, Berlin, GermanyC. is currently with the Department of Psychology, University of Michigan, Ann Arbor.

Address correspondence and reprint requests to Dr. Stephan Niemann, Cecil B. Day Laboratory for Neuromuscular Research, Massachusetts General Hospital (East), Building 114, 16th Street, Charlestown, MA 02129 Niemann.Stephan{at}gmail.com

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.

Supplemental data at www.neurology.org

Editorial, page 662

e-Pub ahead of print on August 15, 2007, at www.neurology.org.

Y.H. receives support from the Ellison Medical Foundation and NIH grants R21NS46421-02 and R01DA17310. K.K.K. receives support from NIH grants P01GM057672 and R01AA009379. R.H.B. receives support from NIH grants 1P01NS31248-02 and R01NS37912, Project ALS, the ALS Association, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel Foundation, the ALS Therapy Alliance and the Angel Fund for ALS Research, and the Muscular Dystrophy Association. P.S. is supported by the Howard Hughes Medical Institute through the auspices of Dr. H. Robert Horvitz, an Investigator in the HHMI.

Disclosure: The authors report no conflicts of interest.

Received January 9, 2007. Accepted in final form April 26, 2007.