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Ppp2r5d Gene Mutation What Is a Gene? What Is Dna? What Does Any of This Mean?

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Ppp2r5d Gene Mutation What Is a Gene? What Is Dna? What Does Any of This Mean? PPP2R5D GENE MUTATION WHAT IS A GENE? WHAT IS DNA? WHAT DOES ANY OF THIS MEAN? BACKGROUND Our body is made up of many different types of cells. Altogether there are trillions of cells in our body. But where do these cells come from? Well, when a mommy and a daddy love each other very much… okay, let’s skip ahead. It all starts with a sperm and an egg. Both the sperm and the egg contain ½ of the genetic material needed to make a human. This genetic material is known as DNA (deoxyribonucleic acid) and is essentially the instruction manual for building everything in our body. This DNA is organized and condensed into chromosomes. Once the sperm and the egg come together we have a complete cell containing 23 chromosomes from dad that match the 23 chromosomes from mom. This cell then starts to make copies of itself, a process called mitosis. CELL DIVISION Mitosis is the process by which a cell duplicates its contents and divides into 2 cells. These 2 cells each undergo mitosis for a total of 4 cells. These 4 cells undergo mitosis, and the process continues and continues. Cells also go through a process called differentiation where they become the different types of cells in our body. Some become bone, blood, skin, nerve, etc. For the sake of this discussion, let’s focus on the part of mitosis that involves DNA replication. DNA REPLICATION DNA replication is the process by which DNA duplicates itself in a cell before the cell divides and equally shares the DNA (in the form of chromosomes) between the two cells. Before we dive into how that happens we have to understand a little more about what makes up a strand of DNA. Nucleotides are the building blocks of DNA. These nucleotides are joined together into long strands and are connected to a complimentary strand running in the opposite direction. There are 4 nucleotides found in DNA; adenine (A), guanine (G), thymine (T), and cytosine (C). Adenine pairs with thymine and guanine pairs to cytosine. These are also referred to as base pairs. To the right is a simple example of a strand of DNA (black) and its complimentary strand (blue). When DNA replicates, the strands separate and new nucleotides are added (red) to each strand until we are left with two complete strands; each containing one old strand and one newly made strand. Okay, we have really long strands of DNA that are made entirely of 4 nucleotides; great… Why again is this important? It is important because DNA encodes proteins, and proteins perform essential functions for our cells. But, how do these long strands of DNA tell me anything? More specifically, how do I get the information to make the PPP2R5D proteins from the DNA sequence? Great questions! www.jordansguardianangels.org @JordansGuardianAngels @JordansGAngels @JordansGuardianAngels 1 CODONS AND AMINO ACIDS To get information from these longs strands of DNA we’ll focus on 3 nucleotides at a time. These 3 nucleotide sequences are referred to as codons. Let’s take our original DNA sequence from the previous page: ATGCTAGCCGTG. This sequence contains 4 codons. ATG CTA GCC GTG. Each of these codons “code” for a specific amino acid. Great, but what the heck is an amino acid?!? Amino acids are the building blocks of proteins. Finally, we’re getting somewhere! Our long sequences of DNA are broken down into smaller, 3 nucleotide sequences which, through the processes of transcription and translation, form long chains of amino acids, aka a protein! This is how our bodies make proteins, including the PPP2R5D proteins. So now you are asking yourself, do we know which codons code for which amino acids, and have we organized these codons into a useful chart? Yes and yes. WARNING: Do not be intimidated by the following chart. Just look it over briefly. To understand how to use the DNA codon chart we will break down each codon into its 3 nucleotides. Let’s take a look at our example sequence codons: ATG CTA GCC GTG The first codon is ATG. To figure out which amino acid this codon is “coding” for we start in the center and work our way out (see below). www.jordansguardianangels.org @JordansGuardianAngels @JordansGAngels @JordansGuardianAngels 2 The codon ATG therefore codes for the amino acid methionine. The next codon, CTA, codes for leucine. The third codon, GCC, codes for alanine. The last codon in our example, GTG, codes for valine. Now we’ve begun building a protein with four amino acids; Methionine- Leucine-Alanine-Valine… This process continues hundreds to thousands of times until the final protein is created. It should be noted that amino acids can be charged (positive, negative, or neutral), and as each amino acid is added to the chain they interact with each other to fold the developing protein into its 3-dimensional shape. This is important because changes in the amino acid sequence could make the developing protein fold abnormally and/or change the final protein’s ability to function properly. So what would make the amino acid sequence change? A genetic mutation. GENETIC MUTATION There are different types of genetic mutations, but for simplicity we are going to stick with a mutation called a point mutation that results in something called missense. With a missense mutation, the DNA sequence has 1 nucleotide that’s been changed, accidentally, and this change results in a different amino acid being put into the chain. Let’s look back at our original example but with a missense mutation added to the third codon: ATG CTA GAC GTG This third codon (using the codon chart above) now codes for aspartic acid instead of alanine, so our developing protein has a different amino acid in the sequence: Methionine-Leucine-Aspartic Acid-Valine… Just one nucleotide has changed this protein’s structure and potentially its functionality. This should sound very familiar to all of us. THE PPP2R5D GENE SEQUENCE AND THE GENETIC REPORT To help understand our genetic report, imagine that the PPP2R5D protein is a long street and we all have an address on that street. Some of us live at 198 PPP street, and others live a few houses down at 251 PPP street. Our genetic reports tell us the address of our mutation and also the change in the amino acid sequence. Let’s use E198K as an example. E198K means that at our address on 198 PPP street, the amino acid with the single letter abbreviation E (glutamic acid) has been replaced by the amino acid with the single letter abbreviation K (lysine). But how?! Let’s look at the codons for glutamic acid and lysine. The codons for glutamic acid are GAA and GAG. The codons for lysine are AAA and AAG. In this case, the first nucleotide for glutamic acid has been changed from guanine to adenine G( AA to AAA, or GAG to AAG). We can do this for the rest of the “variants”. Variant Codon Change Amino Acid Change E197K GAA to AAA Glutamic acid replaced by Lysine E198K GAA to AAA Glutamic acid replaced by Lysine E200K GAA to AAA Glutamic acid replaced by Lysine E420K GAA to AAA Glutamic acid replaced by Lysine R253P CGA to CCA Arginine replaced by Proline W207R TGG to CGG Tryptophan replaced by Arginine E251V GAA to GTA Glutamic acid replaced by Valine Q211P CAA to CCA Glutamine replaced by Proline D251H GAC to CAC Aspartic acid replaced by Histidine D251V GAC to GTC Aspartic acid replaced by Valine D251A GAC to GCC Aspartic acid replaced by Alanine P201R CCA to CGA Proline replaced by Arginine When DNA replicates it does occasionally make errors. Most of the time our body can detect and correct these errors, but sometimes it does not. There are also instances where mutations occur in parts of our DNA that don’t make any significant changes. This is the best case scenario. Unfortunately, this is not the case with the PPP2R5D gene. The PPP2R5D gene is located on chromosome 6, is roughly 27,847 base pairs of our over 3 billion base pairs of DNA, and is considered a highly conserved region of our DNA. In other words, it is small but very important. In most cases that we are aware of, the PPP2R5D gene variation occurred because a random mutation occurred in the gene and was not corrected. This is where we get the term “de novo” or “of new”. The PPP2R5D gene variant was not inherited from mom or dad; but can it be? www.jordansguardianangels.org @JordansGuardianAngels @JordansGAngels @JordansGuardianAngels 3 INHERITANCE Since our DNA is the instruction manual for building everything in our body, and we pass our DNA to our children when we conceive, there is potential to pass the PPP2R5D gene variant to our children. Once a mutation occurs, whether corrected or not, our cells continue to multiply like normal and our body will not recognize the changed DNA sequence as a mutation. The PPP2R5D gene mutation is now just another sequence of our DNA and has the potential to be passed on like our other traits. Congratulations! You made it! Care to learn more? Here are some key terms that should help you: Mitosis Codon Protein Folding Meiosis DNA Transcription Point Mutation DNA Replication DNA Translation Missense Mutation Nucleotide Polypeptide Base Pair Protein Synthesis Additional information about the PPP2R5D gene can be found at: https://ghr.nlm.nih.gov/gene/PPP2R5D# https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R5D And if you made it through all of that, you realize how oversimplified the above explanation is and how lucky we are to have a research team that understands this information (and WAY more) on a level which allows them to actually do something about it.
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