title: 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.
authors.affiliation: Department of Human Genetics, Ruhr University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany. larissa.arning@rub.de
authors.forename: Larissa
authors.initials: L
authors.lastname: Arning
authors.forename: Peter H
authors.initials: PH
authors.lastname: Kraus
authors.forename: Sandra
authors.initials: S
authors.lastname: Valentin
authors.forename: Carsten
authors.initials: C
authors.lastname: Saft
authors.forename: Jürgen
authors.initials: J
authors.lastname: Andrich
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Epplen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001483:Base Sequence; D015331:Cohort Studies; D017931:DNA Primers; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012044:Regression Analysis; D018911:Trinucleotide Repeats
chemical_list: D017931:DNA Primers; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate
references.citation: J Biol Chem. 2001 Jul 6;276(27):24713-8
references.pmid: 11319238
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3872-6
references.pmid: 9108071
references.citation: Annu Rev Physiol. 2000;62:755-78
references.pmid: 10845110
references.citation: Neurology. 1999 Oct 12;53(6):1330-2
references.pmid: 10522893
references.citation: J Neurochem. 1977 Apr;28(4):867-9
references.pmid: 142820
references.citation: Hum Genet. 2004 Apr;114(5):468-77
references.pmid: 14968360
references.citation: Brain. 1987 Dec;110 ( Pt 6):1657-73
references.pmid: 2892568
references.citation: Mol Cell Probes. 1993 Jun;7(3):235-9
references.pmid: 8366869
references.citation: J Med Genet. 1999 Feb;36(2):108-11
references.pmid: 10051007
references.citation: BMC Med Genet. 2004 Mar 24;5:7
references.pmid: 15040808
references.citation: J Neurochem. 1999 May;72 (5):1890-8
references.pmid: 10217265
references.citation: J Biol Chem. 2003 Aug 29;278(35):33364-9
references.pmid: 12810713
references.citation: Science. 1988 Aug 19;241(4868):981-3
references.pmid: 2841762
references.citation: J Comp Neurol. 2000 Apr 17;419(4):407-21
references.pmid: 10742712
references.citation: Neuron. 2002 Mar 14;33(6):849-60
references.pmid: 11906693