Basic Genetics and PXE

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By Ed Ruppert

One cannot discuss this topic without including a respectful nod to Charles Darwin and Gregor Mendel. Although Mendel knew of Darwin’s work, Darwin and the scientific community in general did not recognize the importance of the work of Gregor Mendel - an Austrian monk living in a monastery and working with pea plants.

With his collections of fossils and species of animal life, Darwin was able to argue and show that life on Earth had changed over time, and he believed that his concepts of natural selection and survival of the fittest were responsible - that the great variation of life on Earth had somehow come about through natural processes. By noting the variation that he saw within species, and the fact that man had been successfully breeding animals for many years for desired traits, Darwin realized that change did occur over time and that it occurred through the process of sexual reproduction. What Charles Darwin could not explain was the basis for this change. What was it that caused traits that the environment acted upon? Some traits were successful and were passed on through sexual reproduction to the next generation, while other traits disappeared.

The concept of genes, or factors as Gregor Mendel called them, was unknown at that time. Even though Mendel (1822-1884), and Darwin (1809-1882) were contemporaries, Darwin was not aware of the significance of Mendel’s work. It was left to this monk working alone in a small garden to explain how traits in plants and also in animals were passed on to offspring in a predictable mathematical way through sexual reproduction.

Gregor Mendel is the Father of Genetics - he introduced the world to the concept of the gene and showed how these factors (invisible at the time) are passed on to future generations. Genetics is the science that studies how genes work and how they are passed on to our children and from our children to their offspring and into the future.

We have learned much since the time of Mendel and Darwin. Genes are carried on chromosomes and each species, of plants and animals alike, has its own distinctive number of chromosomes. The human species has 46, and these chromosomes and the genes on them occur in pairs - thus we have 23 pairs of chromosomes and perhaps as many as 30,000 genes on the 46 chromosomes.

Almost every cell in our bodies has 46 chromosomes in its nucleus. Almost - because there are a couple of exceptions. Our mature red blood cells do not have a nucleus or chromosomes, and more importantly, our sex cells also known as gametes (also called sperm and eggs) contain only half the 46 number and thus half the usual number of genes that all of the other body cells contain. We will see in a moment why this is so important. 

The letter N is used to indicate one set of chromosomes and the notation 2N refers to two sets. All the somatic (body) cells have the 2N number or two sets whereas the reproductive cells have the N number or one set. For example, skin cells, liver cells, etc., are 2N whereas sperm and eggs are the only cells that are N. When humans reproduce, the mother’s egg (N) and the father’s sperm (N) unite to make an embryo which is (2N) and all the cells produced as the embryo grows will have the 2 sets of chromosomes (2N) because as cells divide to produce new cells - the two new cells will be exact copies of the original cell. All of this cell division is responsible for growth. The scientific term for this division of cells is MITOSIS.

When a child reaches sexual maturity and starts producing sperm or eggs, a new type of cell division begins. The 2N cells in the testis and ovary begin their own special type of division - this type of cell division is called MEIOSIS and reduces the chromosome number from 2N to N. The result of this is gametes (sperm and eggs) that are now N and have only one set of chromosomes. This reduction of chromosome number maintains the distinctive number of chromosomes for our species. When our children are produced (the sperm’s N set combining with the egg’s N set forms the 2N condition in the embryo) they will have the same number of chromosomes as their parents - maintaining the constant number of chromosomes for our species - 46. 

So we see that our cells receive half their genes from our fathers and half their genes from our mothers. These genes are responsible for our traits: height, eye color, blood type, etc. Sometimes one pair of genes (one gene from dad and one gene from mom) will determine a trait - say blood type.

Let’s follow blood type as an example: say your mother has type A blood and she passes the A gene on to you through her egg, and say your father has type O blood and he passes the O gene on through his sperm. You do not end up with two blood types - you will only have one - either A or O. In this example the A gene is the DOMINANT gene and will hide (mask) the O gene and you will have type A blood. The O gene has not disappeared; it is still in your cells and thus will be in some of your gametes, and even though you have type A blood you may one day produce a child with type O blood because you are also a carrier of the O gene although it is RECESSIVE and is hidden by the dominant A gene. So genes are either dominant or recessive. The recessive genes will be hidden by dominant genes but if there is no dominant gene in the pair the two recessive genes will then make up the pair and the recessive trait will appear in the offspring. 

Frequently in genetic disorders the mother and father are normal (they will not have the genetic problem) because they have the dominant normal gene that is hiding the other abnormal gene of the pair that causes the problem (the recessive one). If both the father’s sperm and mother’s egg carry the recessive gene when they meet and unite at fertilization, the baby will have two recessive genes making up the pair and there will not be a dominant gene to hide the problem gene. These recessive genes will be expressed and the child will have the genetic problem.

A simple array of four squares can be used to examine more closely the genetics that can occur in an embryo that is formed at fertilization. Let’s use the blood type example again. There are four different blood types for this trait: A, B, AB and O. The A and B genes are both dominant genes, and the O is a recessive gene. Let’s look at a couple of examples.

Example 1: One parent has AB blood and the other parent has O blood. Their pairs of genes can be written as: AB and OO (this is before meiosis occurs to make the sperm and eggs which will reduce the chromosome number to N). The AB parent can produce either A gametes or B gametes and the other parent can only produce O gametes during meiosis. By placing the possible gametes of one parent along the top of the array and the possible gametes that the other parent can produce along the side of the array as seen below, one can see not only the possible results of fertilization but also the probabilities for those results.

AB x OO

Remember that the O gene is recessive and is hidden. The four children in the inside boxes in this example will have either blood type A or blood type B. They have a 2 in 4 or 50% chance of having type A and the same odds for type B blood. These parents cannot produce a child with type O blood even though one parent has type O blood. 

Example 2: Say the parents have these genes for this blood trait: AO and BO:

AO x BO 

In this example these parents can produce children with any blood type: A, B, AB or O. There is a 1 in 4 or a 25% chance that a child will be one blood type or one of the other three blood types.

Example 3: Now let’s use PXE in this example. We assume that PXE is carried by a recessive gene and will show up as a genetic disorder in a child only when each parent is a carrier of the recessive gene and each passes the recessive gene to the child via their gametes. The two recessive genes unite at fertilization (when the sperm meets the egg). Let’s use the following letters to follow this through: N = the normal gene, n = the PXE gene. Let’s use an example where both parents do not have the disorder but are both carrying the recessive gene for PXE. Their pairs of genes will be: Nn and Nn.

Nn x Nn 

There is a 3 in 4 (75%) chance that any pregnancy will produce a normal child (NN, Nn, Nn) and a 1 in 4 (25%) chance that any pregnancy will produce a child with PXE (nn). There is a 2 in 4 (50%) chance that a child born to them will not have PXE but will be a carrier of the recessive gene (Nn) for PXE. There is a 1 in 4 (25%) chance that any pregnancy will produce a child who does not have PXE and is not a PXE carrier.

More examples of the presence or absence of the PXE gene in the sperm and/or egg at fertilization follow:

1. One parent has PXE - this parent will have two recessive genes making up the pair of genes for this trait and will be (nn). 100% of the gametes of this parent (sperm or eggs) will carry the recessive gene for PXE and pass the gene on to 100% of his/her children. The other parent is perfectly normal - his/her two genes for the trait will be (NN). This parent will pass the normal, dominant gene on to all of the children guaranteeing that every pregnancy will produce a normal child without PXE (Nn).

nn x NN

The children in this example will all have (Nn). In other words they will all have the dominant gene (N) that will mask the recessive gene (n) and there will be no chance that their children will have PXE (0%). On the other hand 100% of their offspring will be carriers of the recessive gene for PXE (Nn) and will be able to pass this gene on to their children (the grandchildren of the original parents).

2. If one parent is normal but is a carrier of the recessive PXE gene (Nn) and the other parent is perfectly normal and does not have the PXE gene (NN) the following diagram represents this situation.

NN x Nn 

In this example 100% of the children will be normal - every pregnancy will produce a child without 
PXE. There is a 50% chance though that each pregnancy will produce a child who will be a carrier of the PXE gene (Nn) but will not have PXE.

3. In this example let’s assume that one parent is a carrier of the PXE gene (n) but has the dominant normal gene (N) to mask the recessive PXE gene (n) and thus will be (Nn). The other parent will have the PXE trait (nn) and all of his/her gametes will carry the PXE gene.

Nn x nn

There is a 2 in 4, (50%) chance that each pregnancy will produce a child with the PXE trait (nn) and a 2 in 4, (50%) chance that each pregnancy will produce a child who does not have PXE but is a carrier for the trait (Nn).

4. If both parents have PXE they will both have the double recessive pair of genes for this trait (nn) and 100% of their sperm and eggs will carry the PXE gene (n) on to their children. This will be very unusual because PXE is rare and for two individuals with PXE to meet and have children will seldom happen. 

nn x nn

If it did occur though, all of the sperm and eggs of these two parents will carry the PXE gene(n) and at fertilization every pregnancy will result in a child with two recessive genes (nn) - with no dominant gene present - 100% of their children will have PXE. As noted above though - this will be very rare.

Many PXE patients ask if there is a simple inexpensive test to determine if their mate is a PXE carrier. According to Dr. Berthold Struk, there is no such test. He notes that the only meaningful way to determine this is through a family mutation analysis in ABCC6, which if done completely costs about $3000. One could have a skin biopsy of nonlesional skin. If it is positive, one is likely a PXE carrier. If it is negative, it tells you nothing. Thus, the best approach is to draw blood for DNA extraction and mutation analysis. A geneticist can determine the need for a complete mutation analysis for a couple regarding the relative risk of each being a carrier. The geneticist will look at family history, geographic location, etc. In the end, the couple will have to decide their own fear of having a child who has PXE.