Dr. Down's weak-minded chromosome
One Flew Over the Cuckoo's Nest was the title of the novel by the American writer Ken Kesey. A wonderful film was made based on this work. It seems that it was then that many people first heard about Down syndrome, although today very few people know what it really is.
This syndrome was first described by the English physician Langdon Down (John Langdon Haydon Down, 1828-1896). In 1866, in his work Observations on an ethnic classification of idiots, he described the morphological characteristics of people with mental disabilities. Such a child is outwardly different from other children: he has a slanting eye shape, a small head, a flat face, an irregular bite, short arms and legs. He has impaired coordination of movements and poor muscle tone.
In addition to listing outward traits in detail, Dr. Down also noted that children have frequent heart and endocrine defects, and that children with disabilities are learning. Down pointed out the importance of articulatory gymnastics for the development of their speech, as well as the propensity of children to imitate, which can contribute to their learning. Langdon Down correctly established that this syndrome is congenital, but mistakenly associated it with parental tuberculosis. In 1887, Down published a more complete monograph "Mental illnesses of children and adolescents" ("On some of the mental afflictions of childhood and youth"). Later, the syndrome of mental retardation was named after Dr. Down.
Langdon Down mistakenly believed the child's mental disability was related to parental tuberculosis. Today it is known that the risk of having a baby with Down syndrome depends on the age of the mother. Over the years, the number of genetic errors increases, and the risk of having a sick child increases. For women under the age of 25, the probability of having a sick child is 1/1400, up to 30 - 1/1000, at 35 years old, the risk increases to 1/350, at 42 years old - up to 1/60, and at 49 years old - up to 1 / 12. Oddly enough, the age of the maternal grandmother is also important. The older the grandmother was when she gave birth to her daughter, the higher the likelihood that she will give birth to her grandson or granddaughter with Down syndrome
Langdon Down also gave an amazing example of one of his patients who, with a Mongoloid face and other characteristic skeletal disorders, nevertheless had an amazing memory, he read to the doctor huge passages from the fundamental work of the famous British historian Edward Gibbon (1737-1794) "The decline and fall of the Roman Empire." Today, we would note with this example that, unlike Alzheimer's disease, the pathology in Down syndrome does not concern the gyrus of the seahorse, or the hippocampus, located deep in the temporal lobes of the brain and which is the main structure of the limbic system. Damage to the hippocampus in humans impairs memory for events close to the moment of damage, memorization, processing of new information, and the difference in spatial signals.
Third wheel
For almost a century after the description of the syndrome, scientists still could not count the number of human chromosomes. Finally, this was done, and doctors dealing with the problem of downs, to their surprise, found that the pathology of the brain and facial skeleton was caused by the so-called trisomy, or the presence of three chromosomes of the 21st pair. The cause of the disease is a violation of the process of chromosome divergence during the formation of gametes (eggs and sperm), as a result of which the child receives from the mother (in 90% of cases) or from the father (in 10% of cases) an extra 21st chromosome.
Later it turned out that Down's syndrome can also occur in the presence of a normal number of chromosomes of the 21st pair, that is, two. But in this case, a duplication, or doubling, of a section of one of the chromosomes occurs, as a result of which an anamal fragment of a chromosome with an indefinite number of unknown genes appears. Only after the completion of work on the decoding of the human genome began to gradually clear up.
The enzyme is suggestive
The main breakthrough in understanding the genetic nature of the disease was associated with the discovery of an unknown protein. It had pronounced enzymatic properties, discovered during the study of the genetic background for the development of cells of the immune system (T-lymphocytes) after their activation with the help of various antigens. T-lymphocytes include, in particular, "helpers" that help trigger the immune response.
In activated lymphocytes, the concentration of the so-called nuclear factor NFAT increases, which passes from the cytoplasm into the cell nucleus and "turns on" the immune defense genes. One of these genes is a piece of DNA that encodes a protein channel through which calcium ions pass into the cytoplasm. An increase in the concentration of calcium in activated T-lymphocytes triggers their development and division, therefore, the immune process itself.
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Down syndrome is associated with genetic abnormalities in the 21st pair of chromosomes. The recently studied DYRK enzyme, whose gene is located in the immediate vicinity of the “critical zone of Down's syndrome,” plays an important role in this. Art by: Lawrence Berkeley National Laboratory
The RNA interference method, which involves the "interference" of small RNA molecules, which, with the help of specific enzymes, destroy long messenger RNA molecules that carry genetic "commands" from the nucleus to the cytoplasm, made it possible to "turn off" some genes and study the whole process in detail.
It was then that an unknown protein was discovered - the enzyme kinases with a dual function, and it was called "dual specific kinase" (DYRK). On the one hand, it "quenches" the activity of calcineurin, thereby keeping the nuclear factor NFAT in the cytoplasm, and on the other hand, it suppresses the nuclear factor NFAT itself, preventing its activation by other enzymes.
Deciphering this amazing phenomenon has attracted the attention of scientists. Charles A. Hoeffer, M. D. of Baylor College of Medicine, Houston, Asim Dey, University of Texas Southwestern Medical Center, and Their colleagues, in a study published in The Journal of Neuroscience in 2007, noted that the DYRK gene is located on chromosome 21 in the immediate vicinity of the Down syndrome critical zone. It was after the discovery of DYRK that it became clear why, in addition to mental disorders and skeletal abnormalities, immune disorders are also observed in Down syndrome.
The researchers constructed a mouse model of Down syndrome by disabling the NFAT and calcineurin genes. "Turning off" these most important cellular regulators led to the birth of mice with characteristic changes not only in the organism as a whole, but also in the level of their intelligence. Scientists tested the ability of mice to navigate mazes and find safety islands in the pool.
The researchers discovered kinase with dual specificity and calcineurin, which is especially important for the normal development of nerve cells in the frontal lobe cortex, have proven their value in experiments with mice. This discovery also confirms the commonality of the embryonic development of the nervous and immune systems of the developing fetus.
Three chromosomes of the 21st pair. Illustration: National Human Genome Research Institute
Thomas E. Sussan, Annan Yang of The Johns Hopkins University School of Medicine and colleagues have also worked with a mouse model of Down syndrome to understand the mechanisms of cancer growth. In January 2008, the results of their research were published in the journal Nature. We are talking about the so-called protector gene Ars, which normally protects us from adenomatous polyposis of the large intestine, in which glandular polyps grow in the mucous membrane of the large intestine. Mutation of the Ars gene “removes” the protection, thereby opening the way for the degeneration of these cells and the development of tumors.
There was no limit to the surprise of scientists when they found that in hybrids of mice with Down syndrome and mice with the mutant Ars gene, which are predisposed to polyposis, intestinal tumors were observed significantly less - by 44% - than when crossing healthy mice and mice with the mutant gene Ars.
Down mice carried three copies of their chromosome 16, which contains 50% of the homologues of the 21st pair of human genes. Of particular interest were mice with Down syndrome, in the genome of 16 pairs of which there are only 33 human homologues. The Ets gene had the greatest activity among these “33 heroes”, the antitumor effect of which depended on the number of its copies. Its abbreviation stands for "early stages of [cancerous] transformation." Normally, the gene is also a restraining factor for tumor growth, but after mutation, the gene, on the contrary, begins to spur tumor growth, and has long been known as the gene of cancer "promotion". It was discovered in the cells of mammary gland tumors in mice, and then in humans.
As is often the case, new discoveries did not clarify the picture of the onset of Down syndrome, but only confused it even more. Scientists have yet to figure out exactly how the syndrome, manifested in the form of cognitive, skeletal and immune disorders, was suddenly associated with cancer growth. Today it is known that cancer develops mainly against the background of an immune deficiency that increases with age, therefore this disease is also called the disease of old age. At the age of 16, our thymus, or thymus gland, can respond to a hundred million or more antigens. By the age of 60, he only responds to two million. But how is this related to the death of neurons, which, as you know, do not divide at all (only a few stem cells divide), which leads to mental disability.
So far, this is a mystery of our biology, which all the more attracts inquisitive minds because its solution can clarify at least four problems - immune, cancer, skeletal formation and the viability of nerve cells. We can only wait until further research in this direction will lead to the creation of molecular therapy for children with Down syndrome in the early years of their life, when the brain is most capable of changes.
Igor Lalayants, 15.09.2008