Basics: Cells, DNA, Chromosomes, Genes and Proteins

The basic building blocks of life are called cells. There are about 30 trillion cells in your body that make up your organs. Different types of cells, like bone cells, muscle cells, and bloodcells have different locations in the body as well as different functions. An important cell type for GRIN disorder is the nerve cell, or neuron. The neuron is the basic unit of the brain and its function is to send messages all over your body, allowing you to move, remember things, talk, and much more. DNA can be thought of as the “letters” of genetic code that determines all of the properties of your cells. DNA is “written” as a combination of 4 “letters” and the specific combination of “letters” determine your traits, like your eye color. DNA is organized into long strands, which form structures called chromosomes. We have 23 pairs of chromosomes (46 chromosomes) in our cells. Hundreds to thousands of genes are found on each chromosome. Genes are sequences of “letters” of DNA. They are important because a gene carries “instructions” to make a protein. Proteins are very important molecules in the body that each perform a specific function. For example, the NMDA receptor is a protein that functions in learning and memory. The building blocks of proteins are amino acids, which combine in a sequence to make a protein.  

GRIN FACT: The different GRIN genes are located on different chromosomes. For example, the GRIN1 gene is located on the 9th chromosome, the GRIN2A gene is located on the 16th chromosome, the GRIN2B gene is located on the 12th chromosome, and the GRIN2D gene is located on the 19th chromosome.  

How do variants occur?  

Variants may be natural or induced. Variants can be divided into several categories: 

Point mutations (substitutions) – small (but significant) changes often in a single nucleotide base (“letter” of DNA). Some types of point mutations are: 

Missense mutations: The wrong nucleotide (“letter” of DNA) replaced the correct nucleotide within the protein coding region of gene, resulting in the protein having an incorrect amino acid (“building blocks” of a protein). 

Nonsense mutations: The wrong nucleotide (“letter” of DNA) replaced the correct nucleotide within a protein coding gene, creating a stop codon, which is a signal that stops the process of making the protein. The resulting protein will then be shorter than it is supposed to be (truncated). 

Frameshift mutations: The loss or addition of a nucleotide (“letter” of DNA) that shifts the way the sequence is read. This results in the incorporation of the wrong amino acids (“building blocks” of a protein) into the protein beyond the site of the mutation. 

Deletions remove information from the gene. A deletion could be as small as a single base (“letter” of DNA) or as large as the gene itself.  

Insertions occur when extra DNA is added into an existing gene. 

GRIN FACT: Most of the children with GRI disorders have missense variants. These types of variants are the trickiest to interpret as some missense changes might be harmful, while others don’t have any effect on the function of the gene.   

BASICS about GRIN GENES and NMDA RECEPTORS 

The NMDA receptor it is a channel that allows ions (small charged molecules) to enter the neuron (nerve cell) when it is activated. An NMDA receptor is activated when it is bound by glutamate and glycine (or D-serine). The movement of ions (like sodium and calcium) into the cell receiving a message changes the charge of that cell, which allows it to pass on the message. Due to their role in neuron communication, NMDA receptors are particularly important for learning and memory.  

The GRIN genes are part of a gene family called glutamate ionotropic receptor NMDA type subunits. The family consists of: GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A, GRIN3B. These genes each encode a protein subunit, or “section” of the NMDA receptor.   

There are 4 subunits, or “pieces” that make up the NMDA receptor, and all of the subunits are encoded by a GRIN gene. GRIN1 codes for the subunit called NR1 or Glun1; GRIN2A for NR2A or Glun2A; GRIN2B for NR2B or Glun2B; GRIN2D for NR2D or Glun2D, etc. The NMDA receptor is made of two NR1 (or Glun1) subunits and two other subunits.