|
|
     |
|
|
|
by Roberto Zayas
Advances in genetics provide new insight into an entire class of diseases.
The recent decoding of the human genome has changed how we perceive humanity and life on this planet. Although this discovery is controversial, it will give scientists a set of valuable tools that will advance the field of genetic therapy to the point where researchers will be able to find a cure for multiple conditions that are caused by genetic defects.
Watson and Crick's 1953 discovery of the genetic material called DNA opened a new window to the way we understand and treat diseases. DNA contains four nucleotide bases: adenine, cytosine, guanine, and thymine. Two chains of bases combine selectively to form a double helix strand of DNA. This genetic material makes copies of itself to produce new cells.
The replication process is very accurate, but it is not perfect by any means. Every time the replication machine fails to make an accurate copy of the original strand of DNA a mutation is created. Most of the time these errors result in one DNA nucleotide being substituted for another. Also some errors during the replication can lead to expansion of gene segments.
Defects on genes can have serious and even lethal effects. Sickle cell anemia, Huntington's disease, and cancer are examples of genetic diseases that affect millions of people throughout the world. Recent advances in genetics and physiology have led to the discovery of a new class of genetic diseases called channelopathies.
What are channelopathies?
Channelopathies are caused by mutations in types of proteins called ion channels. These proteins move ions through cell membranes. In addition to maintaining the right ion concentration in organs and tissues, ion channel proteins give neurons their electrical properties. Any disruption in the behavior of these ion channels can harm organs, tissues, or the central nervous system. Even when the word channelopathy is not a very common one, estimates suggest that up to 1 in 1,000 persons suffer from some type of channelopathy.
The most common channelopathy
Cystic fibrosis is the leading cause of chronic lung disease in children and young adults. In addition to being the most common channelopathy, cystic fibrosis is also the most common fatal hereditary disorder for Caucasians in the US. About one in 2,000 Caucasians is affected by the disease and one in 25 is a carrier of the cystic fibrosis gene.
Cystic fibrosis targets the lungs and exocrine glands. Characteristics of the disease include thick mucous that clogs airways and secretion ducts leading to infection, inflammation and progressive destruction of the tissue. It is also associated with a high concentration of salt in the sweat. (The latter symptom is documented in many maxims from northern European folklore, such as the one that states, "Woe to the child which when kissed on the forehead tastes like salt. He is bewitched and soon must die.")
Cystic fibrosis is caused by a mutation in a chloride (Cl-) ion channel. If this channel does not work properly the movement of other ions and water is disrupted, leading to the accumulation of salts in some organs or making some fluids extremely viscous because they lack water.
Many treatments for cystic fibrosis are being studied, but one of the most promising is to artificially insert a "normal" gene into the patient. By inserting a copy of the non-defective gene into cells in the lungs using retroviruses (similar to HIV), doctors hope to be able to improve or cure this condition.
Epilepsies as channelopathies
Another channelopathy that many people are familiar with is epilepsy. Epilepsy is a defect of the brain's electrical system. Some types of epilepsy are caused by external factors including head trauma, high fever, drug overdose, brain tumor, or stroke. Other types of epilepsy are inherited. Inherited epilepsy can either be caused by defects during the process of wiring the neurons or by defects on the genes that produce ion channels in the neurons. Different types of epilepsy correspond to two different types of ion channels: voltage gated channels and ligand gated channels.
A voltage gated channel opens when there is a change in the electrical state of the cell membrane. There are different concentrations of ions in the interior and exterior of cells. These differences in concentration combined with the membrane acting as an isolator create an electrical potential. Every time a channel opens ions move across the membrane thus changing the electrical potential.
A ligand gated channel works like a set of locks on a river. Like a set of locks, a ligand gated channel isolates the content of two aqueous bodies. When a molecule binds to a receptor, the gates open and the content of one of the bodies moves to the other through this channel as water flows through open locks.
There are several types of epilepsy that result from problems with voltage gated channels. Problems with the sodium (Na+) ion channel lead to one type of epilepsy called generalized epilepsy with febrile seizure plus (GEFS+). GEFS+, like any epilepsy, is characterized by seizures. These seizures result from genetic mutations that make the neurons hyperexcitable. Neurons send information when a certain electric potential develops; in this disease, defects in the channels to neurons decrease the size of the electric potential needed to send signals. As a result, affected neurons are more likely to fire.
Benign infantile epilepsy results from mutations in the voltage gated potassium (K+) channels. Seizures usually occur in the first few days after birth, but generally all seizures stop after six weeks. Scientists believe that the symptoms of this syndrome disappear because other types of voltage gated K+ channels begin to appear after birth. These K+ channels take over the overall functions of other channels after the sixth week of infancy.
Another type of epilepsy is autosomal dominant frontal nocturnal epilepsy. Although the name is long, it describes the syndrome accurately. Autosomal dominant indicates that the mutations are not sex linked and only one copy of the gene is needed for the manifestation of the disease. Frontal describes the area of seizure activity as shown by brain imaging. Most seizures occur during sleep.
Mutations in the nicotinic acetylcholine receptors (nAChR) are responsible for this disease. The nAChR belongs to the family of ligand gated channels. Different mutations change the way the receptors open and close the channel. These changes lead to hyperexcitability in regions of the frontal lobe. The hyperexcitability can arise in the same way it does in GEFS+, or it can result from the weakening of the neurons in charge of inhibiting the activity of other neurons.
Several approaches are used to treat these epilepsies. One approach uses channel blockers. Channel blockers are molecules that get stuck in the channel and prevent the flow of ions through it. Genetic therapy is potentially another solution to cure these syndromes permanently. As with cystic fibrosis, genetic therapy for epilepsies inserts healthy genes into defective cells or removes defective genes from the affected cells.
Channelopathies that attack muscles
Ataxias are a type of channelopathy that result in the loss of muscle coordination. These neurodegenerative disorders result from ion channel malfunctions in the cerebellum, a part of the brain. Usually, ataxias are caused by mutations in the voltage gated channels regulating K+ and calcium (Ca2+) ion movement. Expansion of DNA nucleotide base pairs is one cause for these channel mutations. The number of nucleotide repeats in one gene varies from person to person. In some people, however, expansion of the cytosine, adenine, and guanine (CAG) repeats in the gene for the voltage gated Ca2+ channels in the cerebellum is responsible for an ataxia. Channel malfunction in the cerebellum causes problems with balance and coordination.
In addition to ataxias, many other channelopathies also affect muscle control. Mutations in the voltage gated Na+, K+, Ca2+, and Cl- channels and the acetylcholine receptors can produce syndromes that affect the tone and strength of muscles, while others can cause muscle paralysis.
One example is the congenital slow channel syndrome. This syndrome is caused by mutations in the nAChR (similar to the ones in the frontal nocturnal epilepsy). These mutations slow ion movement through the channel and lead to variations on the attraction between ligands and receptors. Patients that are afflicted by this syndrome usually suffer from weakness, fatigability, and many of them show degeneration of the muscle fibers.
Muscle channelopathies are usually treated with blockers that are specific to both voltage and ligand gated channels. Again genetic therapy is an approach that in the future might be able to help patients that suffer from these debilitating syndromes.
Channelopathies: Good and Bad
Mutations are known to cause many channelopathies, but it would be a terrible mistake to label all mutations as unfortunate events. Mutations are the basis of evolution. Although these changes sometimes have catastrophic effects on individuals, they can also lead to improvements in the genetic code. Many of the channels that we have in our bodies today evolved from a single type of channel millions of years ago. Channelopathy studies explore not only the pathological effects of these mutations, but also how nature experiments with different alternatives to create improvements for future generations and species.
