Invited reviewClinical and therapeutic significance of genetic variation in the GRIN gene family encoding NMDARs
Section snippets
Diagnosis and phenotyping
Developmental encephalopathies (Paciorkowski et al., 2018) are disorders associated with delayed childhood development, including impairments in cognition, communication, as well as fine motor and gross motor skills. Impairments in sensory systems such as vision and hearing are also often apparent. When these developmental delays involve multiple modalities, they are often referred to as global delay. When developmental delays persist for more than 5 years, they are almost certain to alter the
Genotyping
Whole exome sequencing (WES) is widely considered to be the first stage of diagnostic testing when neurodevelopmental disorders are suspected (Srivastava et al., 2019), which includes individuals who show concerns for developmental delay, intellectual disability, and/or seizures. While gene panel testing typically utilizes the same technology as next generation sequencing, it still has limitations in terms of analysis compared to WES, such as a reduced capability to detect genomic copy number
Classification of variants
Genetic variation in humans differs for each gene, which necessitates statistical analysis to validate gene constraints as well as the susceptibility of each gene for neurological (or other) diseases. One of the more established scores relevant for this is the Z score for missense variants. In addition, a score for the probability of being loss-of-function intolerant (pLI) and for the observed/expected metric (OE) (https://gnomad.broadinstitute.org/help/constraint) are commonly used. A variant
GRIN variants
The GRIN gene family contains GRIN1, GRIN2A-D, GRIN3A-B. Of these, variants in GRIN1, GRIN2A, GRIN2B, and GRIN2D genes have been identified in individuals with various neurodevelopmental disorders (Fig. 1); the association of GRIN2C(Yu et al., 2018) and GRIN3(Santos-Gomez et al., 2021) with disease remains unclear (see Table 1, Fig. 1B). As expected, there are both similarities as well as differences among these genes in terms of the spectrum of genetic variants that appear to contribute to
Clinical characteristics
Patients with GRIN1-related neurodevelopmental disorder show multiple deficits, including ID, epilepsy, hypotonia, and for some individuals, movement disorders. All affected individuals evaluated to date show variable levels of ID:, including 5% mild, 7% moderate, 71% severe, or 17% profound (Platzer et al., 1993b).
Sixty-five percent of individuals presented with epilepsy (Fig. 1C, Table 2). The onset ranges from birth to 11 years of age, and two thirds demonstrated resistance to conventional
Functional assessment of GRIN variants
The determination of how a GRIN variant might alter protein function usually requires electrophysiological and biochemical assays. The goal of these functional assays is to determine whether a variant results in a loss-of-function (LoF), a gain-of-function (GoF), does not influence receptor function, or produces some complex mixture of effects on protein function. NMDARs have many different functional properties, so testing typically needs to be a comprehensive evaluation of agonist potency,
In vivo models of GRIN variation
In an effort to move a step closer to human physiology, the generation of mouse models containing human-specific variants allows for the detailed exploration of GRIN variants. More specifically, genetically-modified mice are essential for the elucidation of how these variants impact the brain on a developmental, circuit, cellular, and molecular level, as well as provide investigators with a mammalian platform for testing therapeutic approaches. Although homozygous null (knockout) mutations for
Preclinical pharmacological studies
Given that a GRIN variant can often be defined as gain or loss of function, how best can pharmacological modulation be identified that can alleviate symptoms? Pharmacological modulation of clinical symptoms secondary to modulation of NMDAR properties could be beneficial if, and only if, current symptoms are actively being mediated by the GoF or LoF for the NMDAR. However, this is likely an overly simplistic viewpoint, and it seems almost certain that compensatory changes and/or maladaptive
Human studies
Multiple pathogenic variants in GRIN genes have been described as GoF or LoF for the NMDAR, which provides clinicians with opportunities to potentially mitigate dysfunction through the use of either NMDAR-specific blockers/inhibitors or enhancers/potentiators. An initial proof of principle was established by treating a male individual with early-onset epileptic encephalopathy and drug-resistant seizures due to a pathogenic de novo GOF missense variant in GRIN2A (p.L812M) with the FDA-approved
Disclosures
- (a)
Clinical trials sponsored by Rett Syndrome Research Trust, Neuren, Acadia, Ovid, and Marinus. He has consulted for RettSyndrome.org, AveXis, Ovid, Takeda, and Marinus. Additional unrelated funding support from NIH
- (b)
JL: Member of SAB for CureGRIN Foundation, GRIN2B Foundation.IK: none
- (c)
None reported
- (d)
SFT: Member of SAB for Sage Therapeutics, Eumentis Therapeutics, CureGRIN Foundation, GRIN2B Foundation. Co-founder of NeurOp Inc, and Agrithera Inc, PI on grants to Emory from Janssen and Biogen, and
Acknowledgements
(a) CURE, GRIN2B Foundation, Simons Foundation, and Ponzio Family Chair in Neurology Research/Children's Hospital Colorado Foundation.
(b) None reported.
(c) CIHR MOP119298.
(d) NINDS NS111619 (SFT) and NS113530 (CRC), NICHD R01HD082373 (HY), GRIN2B Foundation (HY), Simons Foundation (SFT).
(e) CURE, GRIN2B Foundation and Simons Foundation.
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