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"Confetti Skin, Beauty Within" is our blog about ichthyosis and its effect on our lives. Rachel and our three boys are affected with the form of ichthyosis called "icthyosis en confetti, type 2".

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Here's our summary of our best and most important posts of 2012.

Genetics Part 3: X-linked Ichthyosis

Every person has 23 pairs of chromosomes in every cell. Chromosomes are long strings of DNA that get copied into proteins to make your body run. 22 of them are called autosomal chromosomes, which means that they are matched pairs. The remaining pair is the sex chromosome. Typically, females have 2 X chromosomes, while males have one X (from the mother) and one Y chromosome (from the father). The Y chromosome is very small, accounting for about 2% of all DNA, and somewhere between 70-200 genes of the estimated 25,000 genes we carry.  Most of the known genes on the Y chromosome have to do with making a male body and very few problems are associated with Y-linked mutations.

The X chromosome, however, is very interesting. Because males only get one copy of the X chromosome, whatever is on it essentially functions as a dominant gene in males. Only females can have dominant or recessive expression because they get two copies of the X chromosome, but it isn’t dominant or recessive in the same way that any other chromosome has dominant or recessive genes.  The X-chromosome also undergoes a process called lyonization, or X-inactivation, where every cell basically chooses one or the other copy of a gene on X chromosome and just uses that one for your entire life. Even more confusing, not every gene on the X chromosome is subject to inactivation. And still more confusing, some genes have sections on them that trigger one chromosome to activate most of the time while the other copy is almost never selected. Some genes work no matter which chromosome they came from, even if they are on the inactivated chromosome.

Calico cats are an example of this – some hair cells are using the hair color gene on X chromosome from the father, while others use the X chromosome hair color gene from the mother, resulting in a mixture of colors of cat fur. Male cats only get one hair color gene from the mother, so they are whatever color the inherited gene dictates that they should be. And like some calico cats are mostly brown while others are mostly orange, you can have as much variation in human x-linked traits. Women can be completely colorblind, or only have hints of carrying the trait. Women can show signs of male pattern baldness without actually going bald. Instead of developing a completely hairless patch on top, a la Sean Connery, the hair just thins out all over the head, or have no symptoms of that gene at all.

There are two types of ichthyosis that are caused by X-linked genes: One is, obviously, X-linked ichthyosis, a very common recessive variety that only very rarely affects females, and the other is an extremely rare syndrome that affects only females called CHILD syndrome.

The affected father passes the STS mutation to his daughters, but his sons are unaffected.

The affected father passes the STS mutation to his daughters, but his sons are unaffected.

X-linked ichthyosis is caused by a gene called STS – it is a gene that makes an enzyme called Steroid Sulfatase. It is one of the genes on the X chromosome that is never inactivated. So unlike the calico cat, as long as one functioning copy of the gene is in a person,  that person won’t ever have signs of X-linked ichthyosis. Since men only get one copy, if it is mutated, they will have x-linked ichthyosis. If it is not, they will have normal skin. Women would only have x-linked ichthyosis if BOTH copies were mutated.

Have you ever heard people say that they thought certain traits skipped generations? I’ve heard it asked about it regarding everything from red hair to Alzheimer’s to having twins. . Recessive traits seemingly appear out of nowhere and vanish in the next generation. Common recessive types, like blue eyes or blond hair, come and go in what seems like a sporadic fashion. And in X-linked disorders, it certainly appears that traits literally skip generations, passing from grandfather to grandchild. But genes really can’t skip generations. They are either passed on or they are not, and whether they are expressed just depends on what the other parent passed on to the same child

Let’s say a father has X-linked ichthyosis (X’Y). He passes the affected X’ gene to only his daughters. His sons get his Y chromosome. So long mom isn’t a carrier, the girls end up as X’X and the boys get XY. Every child has at least one functioning copy of STS, so no child has X-linked ichthyosis, and the boys cannot pass it along to their children. (See the picture on the right.)

The mother is a carrier and each son has a 50% chance of being affected. Each daughter has a 50% chance of being a carrier.

The mother is a carrier and each son has a 50% chance of being affected. Each daughter has a 50% chance of being a carrier.

However, those girls have X’X, and when it comes time for them to have children, each child has a 50% chance of getting the mutated STS gene, X’. Assuming that their husbands do not have X-linked ichthyosis, (see the picture to the left) their girls will be a mix of X’X and XX, all unaffected because there is at least one working copy. But the boys will be a mix of X’Y and XY. The ones with X’Y do not get a working STS gene and thus are born with X-linked ichthyosis.

Now, if mom is a carrier AND dad has X-linked ichthyosis, their genetics look like this: X’X and X’Y. All the girls will get X’ from dad. They have a 50% chance of getting X or X’ from mom. Half will be X’X carriers of the gene, but normal skin. Half will have X’X’ – females with X-linked ichthyosis. Likewise, the sons get Y from dad and have a 50% chance of getting X or X’ from mom. The XY boys will have normal skin and cannot pass the disorder on. The X’Y boys will have X-linked ichthyosis. This situation is pretty rare because not that many in the population have the STS mutation, so having a couple marry where one has X-linked ichthyosis and the other is a carrier is pretty unlikely.

How would you know if you’re a carrier? You can’t know for certain unless a child is born affected. But you are at risk if you are a daughter of an affected father, or your mother is the daughter of your affected grandfather. It is entirely possible that X-linked disorders can pass unseen through several generations of women and suddenly reappear in a great-great-grandchild from the affected ancestor.

 

 

 

 

This is a series of posts on genetics. More information is available in the following links:
Genetics 1: What’s a Gene?
Genetics 2: Recessive Inheritance
Genetics 3: X-Linked Inheritance (X-linked Ichthyosis)
  <–You Are Here
Genetics 4: X-Linked Inheritance (CHILD Syndrome)
Genetics 5: Dominant Inheritance
Genetics 6: Mosaicism
Genetics 7: Video explanation of how mutations work
Genetics 8: Why we don’t do automatic prenatal screening for ichthyosis

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