Ichthyosis Research (2002)

*Peter M. Steinert, PhD,
Chief, Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD

Ichthyosis diseases result from mutations in genes that encode structural proteins or enzymes that are needed to build a normal epidermis on the outermost layer of our skin. Every one of us has two copies of each gene (one gene copy per chromosome) in all of our cells, including epidermal cells. Some diseases arise when a mutation occurs in one gene copy. These are called autosomal dominant diseases, because the bad protein/enzyme made from one mutated gene interferes with the normal copy, and thereby destroys the function of an epidermal cell. Very often autosomal dominant diseases involve genes for structural proteins. An example is epidermolytic hyperkeratosis (the keratin 1 or keratin 10 genes). Other ichthyoses occur when both gene copies are mutated, so that the products from both copies are bad. Many of these are autosomal recessive diseases, and commonly involve enzymes. An example is lamellar ichthyosis (the transglutaminase 1 gene).

We all have 23 pairs of chromosomes. Each chromosome carries hundreds or thousands of genes. And each gene consists of a code made up of strings of thousands of DNA nucleotides. When the cells in our bodies divide for normal growth, the entire chromosome and all of its DNA is copied. Even though the error rate of copying DNA is very very low, errors do occur. If copying errors occur in reproductive cells (a sperm or an egg), then there is a chance that a mutation will be passed along to our children. Probably each one of us carries several mutant genes caused by copying errors. Mercifully, many errors are ‘silent’, so that we live perfectly normal lives blissfully unaware of their existence. Very rarely however, the errors affect an epidermal gene, and so unfortunately, a new or ‘spontaneous’ occurrence of an ichthyosis disease appears simply due to a copying error in germ cells (the reproductive cells). Also, the natural gene copying process is so efficient that defective genes from our parents are faithfully but regrettably copied and can be passed along to our children.

Based on the simple chance of which gene copy is passed along, the possibility of inheriting an autosomal dominant disease from our parents can be more than 50%, and an autosomal recessive disease, 25% or more. These germline mutations will affect every epidermal cell over our entire bodies. That’s why most of the skin is affected in an ichthyosis disease. Of course DNA copying errors also occur after fertilization in ‘somatic’ cells (all other cells in the body), but usually these somatic mutations are never noticed because the single sick epidermal cell simply falls off without affecting the whole skin at all.


Genes for making a normal epidermis fall into three types. The first are the specific genes, like keratins, transglutaminases, and many others. (Liver, bones, nerves, etc, each need hundreds of specific genes also, but they are different from epidermis-making genes.) Then there are other genes (we don’t have any idea how many yet, but it may be hundreds) that are used to control, like traffic lights, the actions of the specific genes. I bet that some of these controllers can become mutated too, resulting in an ichthyosis disease. Finally, there are “housekeeping” genes, which are used for routine non-specific stuff in all cells, like copying DNA, making proteins, shuttling thingsaround inside our cells, gossiping with neighboring cells, etc. If there were a mutation in any of these, a cell will quickly perish.

Current basic research in ichthyosis diseases falls into three broad categories. The first is what I shall call ‘discovery’ research. Here, scientists are actively trying to discover all of the genes that are required to make a normal epidermis. When the first draft of the human genome sequence was published recently, we found out that there are large numbers of epidermal genes no one knew about before. Many of these are grouped together on chromosome 1 with known epidermal genes such as filaggrin and loricrin. At present no one has a good idea on what all these new guys do. So the goal of ‘discovery’ researchers is to try to figure out what they do. Are they always used in normal epidermis? Are they backups that are used when a normal epidermal gene is mutated? Do they protect us from the damaging effects of ultraviolet light and sunburn?

Another aspect involves discovery of the nature and function of the genes that control the specific genes. Who are these? What do they do? When do they do it? You may have heard or read about DNA chips. These are tiny high-tech devices used to identify all of the genes used in a particular tissue during its growth and function. Several teams worldwide are working on epidermal genes. My understanding is that thousands of genes are used to make the epidermis. This great complexity will take time to sort out. Potentially, mutations in any one of these could cause disease, or offer a window of opportunity for treatment.

There have been great advances made just within the last 10 years in the identification of the genes that cause some types of ichthyoses. However, many still need to be solved, such as ichthyosis vulgaris, and many types of diseases grouped together as congenital recessive ichthyoses. Thus the second category of current research is to continue this work for all ichthyosis diseases. Some of them may be ‘complex’ diseases. Such diseases occur because there are mutations in more than one gene affecting the epidermis at the same time. Psoriasis is an example of a notoriously complex multi-gene skin disease. Once we know these details, physicians and scientists can design specific diagnostic tests. The third category of current basic research concerns what scientists are now trying to do to treat ichthyosis diseases for which the involved gene is already known. The favored approach by many investigators worldwide involves gene therapy. In principle, this is a simple idea: why not just replace the defective gene with a normal copy? In practice, however, this is very hard to do. Yes, we can clone a normal gene, but how do we effectively get it into the affected epidermal cells? Scientists have made progress with modified harmless viruses that can ‘infect’ cells with the normal gene. One difficulty with this method is that the epidermis is a constantly renewing tissue, so that cells would have to be infected with these viruses every few days. But epidermal cells grow from stem cells hidden deep inside the epidermis. Thus one hot research topic is to try to specifically find and infect the stem cells so that all new epidermal cells will always have two normal gene copies.

Another problem we have to deal with in autosomal dominant ichthyosis diseases is that the product of the one bad gene copy is often enough to destroy the normal life of the epidermal cell. So, we have to find a way to switch off the bad gene, or switch off the cellular machinery that makes the bad protein. We already know that the 50% of protein or enzyme made from the one normal gene copy is usually enough for the epidermal cell to live comfortably. So scientists are hard at work and there are promising ideas on the horizon. One is the use of an artificial thing called a ribozyme. This is a small piece of synthetic RNA which can act like a specific knife. When all cells decide to make a protein from a gene on a chromosome sitting in the nucleus, the gene is first copied as a piece of RNA. This RNA is then decoded into a protein or enzyme. Ribozymes can be designed to specifically destroy a piece of RNA bearing an evil mutation. In theory, this will stop the production of a bad protein or enzyme, so that the other normal 50% can work without interference. A ribozyme to cure an occurrence of epidermolytic hyperkeratosis could be added to the skin in some sort of liposome cream, similar to what are used in cosmetics.

A third approach is being tested for autosomal recessive enzyme diseases where both copies are bad. Scientists have learned how to make buckets full of normal epidermal enzymes, such as transglutaminase 1. The challenge now is to find how to resupply it back to the epidermal cells. Again, they are trying all sorts of liposomes to package the normal enzyme for proper delivery.

Many of us in the research community have committed our entire research careers to not only finding the genes at fault in various ichthyosis diseases, but also to finding the simplest and best way for effective treatment.

* Dr. Steinert passed away on April 7, 2003

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