A report published online October 3 in Nature Genetics adds to the evidence for functional variants in NMDA glutamate receptor genes playing a role in neurological disorders. Researchers in Europe have found six new mutations—four in GRIN2B (which encodes the NR2B subunit) and two in GRIN2A (which encodes the NR2A subunit)—in their search for genes causing mental retardation and epilepsy. The findings come just months after scientists reported identifying a GRIN2B variant as a potential risk factor for Alzheimer disease in their analysis of AD Neuroimaging Initiative (ADNI) participants (Stein et al., 2010 and ARF news story).

Dagmar Wieczorek of University Hospital Essen and Kerstin Kutsche of University Medical Center Hamburg-Eppendorf, both in Germany, and Lionel Van Maldergem of the University of Liège, Belgium, jointly directed the new research. Co-lead authors were Georg Rosenberger in Hamburg-Eppendorf and Sabine Endele of the University of Erlangen-Nuremberg, Germany.

The scientists homed in on GRIN2B after breakpoint mapping experiments revealed chromosomal translocations that disrupted this gene in two unrelated, mentally retarded boys. Similar analyses uncovered a third translocation, this one disrupting the GRIN2A gene, in a man with mental retardation and epilepsy. “In light of the crucial neuronal function of NMDA receptors, we hypothesized that disruption of GRIN2B or GRIN2A underlies the neurological phenotypes in these three individuals with chromosome aberrations,” Rosenberger explained in an email to ARF.

He and colleagues sequenced the GRIN2B gene in 468 other people with mental retardation, and screened for GRIN2A variants in a separate cohort of 127 people with both mental retardation and epilepsy. These analyses turned up four GRIN2B point mutations and two mutations in GRIN2A. Doing some electrophysiology with frog eggs that express one of the NR2A variants, the researchers measured reduced Ca2+ permeability and a loss of the Mg2+ block, suggesting that the mutation disrupts neuronal electrophysiology.

Might the newly identified mutations be related to AD as well? Probably not, notes Jason Stein, University of California, Los Angeles, who was first author of the aforementioned study identifying a GRIN2B variant as a potential AD risk factor in the ADNI cohort. “Though this study shows a severe phenotype resulting from a single mutation, late-onset AD is commonly thought to be a multi-factorial disease, which results from carrying many risk alleles, each lending a small predisposition to the development of the disease. As such, it is unlikely that the specific variants identified here are also related to AD,” Stein wrote.

There could be a less direct tie-in with AD. The variant reported by Stein and colleagues falls between exons 2 and 3 of GRIN2B, close to one of the causative mutations identified in the new study, he noted. “This suggests that more common variants in the same gene, like the one we identified, may have effects similar but more subtle than those identified in this paper,” Stein wrote. (See full comment below.)

The potential connection with AD finds support from a study suggesting that Aβ peptides decrease the number and activity of NMDA receptors (Snyder et al., 2005 and ARF news story). Furthermore, though some studies have found no association between GRIN2B variants and AD (see, e.g. Seripa et al., 2008), a recent analysis reported that several GRIN2B polymorphisms do correlate with sporadic AD (Jiang and Jia, 2009). The current findings, as well, “predict a reduced amount of the NR2B or NR2A receptor subunit in most mutation-positive individuals with mental retardation and/or epilepsy,” Rosenberger wrote. “Taken together, these data and our findings may support the idea that any disturbance in the number and/or composition of NMDA receptors has profound effects on neuronal development and activity in humans, and causes various neurological diseases such as mental retardation, epilepsy, and possibly AD/neurodegeneration.”—Esther Landhuis.

Reference:
Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, Milh M, Kortuem F, Fritsch A, Pientka FK, Hellenbroich Y, Kalscheuer VM, Kohlhase J, Moog U, Rappold G, Rauch A, Ropers HH, von Spiczak S, Toennies H, Villeneuve N, Villard L, Zabel B, Zenker M, Laube B, Reis A, Wieczorek D, Van Maldergem L, Kutsche K. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nature Genetics. 3 October 2010. Abstract

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  1. This study is extremely interesting because it identifies rare functional variations that lead to mental retardation and epilepsy in genes encoding NMDA receptor subunits. Here mutations in the GRIN2B gene are identified and cause moderate to severe mental retardation and brain structure anomalies. Though this study shows a severe phenotype resulting from a single mutation, late-onset AD is commonly thought to be a multi-factorial disease, which results from carrying many risk alleles, each of which lends a small predisposition to the development of the disease. As such it is unlikely that the specific variants identified here are also related to Alzheimer's.

    However, this study does demonstrate that variations in the coding sequence of the GRIN2B gene have serious consequences on the structure and function of the brain. In our work, we found that a variant in the non-coding region of the same gene between exons 2 and 3 (which is close to one of the causative mutations identified in this study) is associated with subtle differences in temporal lobe volume and slight predisposition to development of Alzheimer's disease. This suggests that more common variants in the same gene, like the one we identified, may have effects similar but more subtle than those identified in this paper. The subtle effects might lend risk to neurodegeneration and subsequent development of Alzheimer's disease.

References

News Citations

  1. Obesity Gene Depletes Brain Reserves, May Raise Alzheimer’s Risk
  2. Amyloid-β Zaps Synapses by Downregulating Glutamate Receptors

Paper Citations

  1. . Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease. Neuroimage. 2010 Jun;51(2):542-54. PubMed.
  2. . Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.
  3. . Association analysis of GRIN2B, encoding N-methyl-D-aspartate receptor 2B subunit, and Alzheimer's disease. Dement Geriatr Cogn Disord. 2008;25(3):287-92. PubMed.
  4. . Association between NR2B subunit gene (GRIN2B) promoter polymorphisms and sporadic Alzheimer's disease in the North Chinese population. Neurosci Lett. 2009 Feb 6;450(3):356-60. PubMed.
  5. . Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010 Nov;42(11):1021-6. PubMed.

External Citations

  1. ADNI
  2. GRIN2B

Further Reading

Papers

  1. . Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010 Nov;42(11):1021-6. PubMed.
  2. . Association between NR2B subunit gene (GRIN2B) promoter polymorphisms and sporadic Alzheimer's disease in the North Chinese population. Neurosci Lett. 2009 Feb 6;450(3):356-60. PubMed.
  3. . Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease. Neuroimage. 2010 Jun;51(2):542-54. PubMed.
  4. . Association analysis of GRIN2B, encoding N-methyl-D-aspartate receptor 2B subunit, and Alzheimer's disease. Dement Geriatr Cogn Disord. 2008;25(3):287-92. PubMed.

Primary Papers

  1. . Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010 Nov;42(11):1021-6. PubMed.