GRIN2B

GRIN2B is a gene located on the short arm (called p) of the 12th chromosome 12p13.1. It is the gene encoding the human GluN2B protein. The protein is a member of 7 gene families, which are: GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A and GRIN3B. The proteins encoded by these genes together form a receptor (NMDA receptor), which is responsible for sending chemical messages between neurons in the brain. Therefore, GluN2B protein exists in nerve cells (neurons) of the brain, mainly in the developmental process before birth. Existing studies have shown that GluN2B protein constitutes a component (subunit) of the special protein structure of the NMDA receptor. Among them, the NMDA receptor is a glutamate-gated ion channel. The available data indicate that there are several types of NMDA receptors, composed of different protein combinations.

Figure 1. The crystal structure of GluN2B protein. (Yuto Takasaki, et al.; 2016)

These receptor channels can be opened/closed, and this process is accompanied by the sending and receiving of signals in the brain. When a molecule called glutamate binds to them, these channels are opened. When the gated channel is at rest, the receptor is closed and blocked by magnesium ions. At this time, no signal can pass through the closed door. When glutamate binds, this will turn off the magnesium blocker and turn on the receptor (called the activated state). The NMDA channel opens, allowing positively charged particles (cations) to flow through. On the one hand, the flow of cations activates (stimulates) neuron signal transmission, on the other hand, this process also plays an important role in the process of neuron maturation to complete a specific function (differentiation). Therefore, NMDA receptors are involved in normal brain development, changes in the brain's response to experience (synaptic plasticity), learning and memory.

GRIN2B and Disease

If the GRIN2B gene changes, it will be classified as a gain-of-function mutation or a loss-of-function mutation. Among the mutations that gain function, the receptor is more active than the normal receptor. This means that the time it takes to turn on has increased, or the signal is too strong. This affects the brain's ability to receive signals and can cause neurodevelopmental problems. Too many signals may cause the brain to become over-excited, which affects the way it connects and may cause seizures. Loss-of-function mutations will cause the signals between neurons to not be transmitted normally, and then cause movement disorders.

GRIN2B-related Neurodevelopmental Disorder

Dozens of mutations in the GRIN2B gene have been found to cause GRIN2B-related neurodevelopmental disorders, which are characterized by intellectual disability, delayed language and motor skills development. Other neurological problems common in this disease include seizures, hypotonia, movement disorders, and behavioral problems. Many GRIN2B gene mutations result in the production of non-functional GluN2B protein or prevent one copy of the gene in each cell from producing any GluN2B protein. The lack of this protein may reduce the number of functional NMDA receptors, thereby reducing the receptor's activity in the cell. Other mutations cause abnormal GluN2B protein production, which may alter the function of NMDA receptors. Studies have found that some of these mutations reduce NMDA receptor signaling, while others increase it. Researchers are not sure how abnormal activity of NMDA receptors prevents normal growth and development of the brain, or why too much or too little activity causes similar neurological problems in people with grin2b-related neurodevelopmental disorders.

In addition, GRIN2B related diseases also include epileptic encephalopathy, type 6 mental retardation in infants and young children. This neurological disorder is usually characterized by low muscle tone, developmental delay, seizures, and slurred speech. The range of symptoms is wide, depending on the exact genetic variation. Although GRIN2B-related diseases can be inherited from parents to children, most GRIN2B cases are non-inherited (from the beginning) and have no family history. People with mutations are autosomal dominant genes, which means they have a 50% chance of passing the mutation to any offspring.

References

1. Bell S, et al.; Disruption of GRIN2B Impairs Differentiation in Human Neurons. Stem Cell Reports. 2018, 11(1):183-196.
2. Fedele L, et al.; Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat Commun. 2018 Mar 6;9(1):957.
3. Freunscht I, et al.; Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene. Behav Brain Funct. 2013, 9:20.
4. Hu C, et al.; Human GRIN2B variants in neurodevelopmental disorders. J Pharmacol Sci. 2016, 132(2):115-121.
5. Swanger SA, et al.; Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains. Am J Hum Genet. 2016, 99(6):1261-1280.
6. Yuto Takasaki, et al.; Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. Sci Rep. 2016, 6:33311.