Genetic aspects of skin diseases
Hereditary skin diseases, or genodermatoses, as skin doctors call them, have always aroused the interest of ordinary people, following the legends and fairy tales about the "elephant man", "wolf boy" and "hedgehog people". Medicine has long considered these diseases extremely rare, of limited interest, and as a rule incurable.
In recent years, the attitude towards this group of diseases has completely changed. It became known that hereditary skin diseases are not at all rare: Ichthyosis Vulgaris or ichthyosis (a disease in which the skin is covered with scales) occurs in 1:100 – 250 cases, and carriers of Epidermolysis Bullosa Simple (blistered skin formed as a result of a structural violation of the basement membrane connecting the epidermis with the dermis) are about 1% of Americans.
At the same time, over the past decade, the understanding of the genetic base of most genodermatoses has advanced far, thanks to which the possibility of prenatal diagnosis and genetically competent family planning has opened up to patients and their families. And medications (for example, retinoids) and the first clinical trials of gene therapy show that a considerable part of these diseases can be treated, although not always with an ideal result.
Hereditary skin diseases in the Middle East
Despite the breakthrough in unraveling the molecular basis of many hereditary skin diseases, there is still much to learn about them. It is curious that this fact was found out mainly in the course of studies of hereditary skin diseases in our region. As you know, there is a peculiar composition of the population in the Middle East, peoples do not mix with each other, but related marriages are often concluded. Such cases are characterized by a high proportion of genetic diseases that occur when non-sex chromosomes (so-called autosomes) meet from the father and from the mother, each of which carries a defect. If in ordinary marriages the probability of meeting such altered chromosomes is extremely low, then in the case of a related marriage it increases dramatically. This genetic anomaly is a recessive trait and can manifest itself only if it is received from both parents.
This explains the unusual picture associated with Epidermolysis Bullosa Simplex disease, which is inherited dominantly in most parts of the globe, but a third of cases in our region are recessive, which implies the need for genetic family planning in the risk group. Numerous related marriages are not only associated with a high proportion of recessive gene damage, but also usually lead to the accumulation of genetic defects characteristic of this population group and the corresponding spectrum of diseases.
In recent years, several diseases characteristic of the ethnic groups of our district have been described in this way, for example, Normophosphatemic Familial Tumoral Calcinosis. This disease was first noted by Dr. Arie Metzker, senior physician of the skin department of the Tel Aviv Medical Center; it is characterized by calcium deposition in various parts of the body. So far, the disease has been described only among people from Yemen.
A tool for learning the basics of biology
The primary goal of the study of the genetic base of the hereditary syndrome is to develop the possibilities of diagnosis, prevention, and sometimes treatment of the disease for the benefit of the patients themselves and their families. The study of these diseases caused by a malfunction in one gene, and therefore disrupting the function of only one protein, brings secondary benefits, expressed in an unambiguous characterization of the function of the protein affected by the disease. For example, it has recently become known that CEDNIK syndrome, which includes Ichthyosis and a serious neurological disorder, comes from the impaired function of the tiny SNAP29 protein from the SNARE family. CEDNIK syndrome has been described today in only six people around the world, but deciphering the genetic glitch has helped to understand the basic aspects of human skin formation. The situation is similar with the interpretation of ANE Syndrome, a disease that combines disorders in the development of hair and the nervous system. Here, the importance of the ribosomal assembly process for the proper development of the hair follicle, the nervous system and some components of the endocrine system was revealed.
From rare diseases to frequent
These cases illustrate the value of the study of rare diseases (known in the literature as Orphan Diseases), except for the direct benefit of patients and their loved ones. The most impressive achievement in this field is the aforementioned unraveling of the genetic base of Ichthyosis Vulgaris.
In 2006, it became known that this disease is caused by the absence of the protein filaggrin, which strengthens the epidermal barrier and separates the body from the outside world. Since years before it was known about the epidemiological connection of Ichthyosis Vulgaris and Atopic dermatitis, one of the most common human diseases, it was suggested that the absence of filaggrin is probably the cause of Atopic dermatitis.
In less than a year, about a dozen studies have been published that proved beyond any doubt that mutations in the gene encoding filaggrin cause a clear tendency to Atopic dermatitis and asthma among patients. Since filaggrin is the central component of the epidermal barrier, it is likely that the absence of this protein opens the way through the skin to the immune system to various antigens from the environment, and as a result, an incorrect immune reaction appears, characteristic of Atopic dermatitis. Recently, this hypothesis has been confirmed by experiments on animals.
It is important to mention that this discovery fundamentally changes all our ideas about Atopic dermatitis. Until recently, Atopic dermatitis was considered an immune multifactorial disease; and today the prevailing opinion is that the disease is actually caused by a primary lesion of the epidermis, and most importantly, that the disease is monogenic with partial permeability.
The new results also have therapeutic value. Most of the common mutations that cause this disease are of the nonsense type (interrupt the translation of filaggrin). It was recently found out that drugs from the group of immunoglycosides, in addition to antibacterial action, contribute to the resumption of protein translation even with DNA affected by a nonsense mutation. Recent clinical studies with local use of immunoglycoside derivatives in patients with Atopic dermatitis have shown very encouraging results.
Genetics and composite properties in dermatology
With the development of new methods of molecular biology and bioinformatics, the study of monogenic diseases has become relatively simple in recent years. On the other hand, it is still difficult for us to cope with much more common genetic properties, known as composite. We are talking about diseases or physiological properties that are influenced by multiple genetic factors, each of which makes a small contribution to the manifestation of the property, and their combination and interaction with the environment determine the final result. These properties are familiar to all of us: height, general health, high blood pressure, type II diabetes, etc.
In dermatology, it is known that relatives of patients with psoriasis have an increased risk of getting sick compared to the average level. This fact, and the fact that monozygotic twins are more likely to get psoriasis together than dizygotic twins, formed the basis for many studies that in recent years have been looking for genes that cause a predisposition to psoriasis, a disease affecting from one to three percent of the population.
To date, many sections of chromosomes associated with the disease and several suspicious genes have been identified. It should be mentioned that all these data require confirmation by additional studies. In addition, despite the encouraging results, this success has not yet affected the treatment of the disease. Recently, several new extensive studies have been launched. It can be assumed that an increase in the number of patients studied will make it possible to accurately identify genetic factors important for the pathogenesis of the disease, to which subsequent treatment will be directed.
Another topic of great interest to geneticists is the variety of reactions to medications. In dermatology, serious efforts are also being made to search for genetic (pharmacogenic) characteristics that can predict side effects and therapeutic effect. Recently, for example, several differences have been found in the genes encoding the carrier proteins of the drug Methotrexate, which differences correctly predict the side effects and therapeutic effect of this drug, often used against psoriasis.
Conclusion
Hereditary skin diseases have evolved in recent years from a secondary topic to an important focus of basic and clinical research. This fact is reflected in the number of articles on this topic published weekly in leading scientific journals. There is no doubt that genetics has an important role in solving the pathogenesis of many common skin diseases with a family predisposition, as well as in the development of new ways to treat these diseases.MedServer.co.il