Genetic variant of calcium channels could be an underlying cause of ALS
We all marvel at the athletic dexterity of the Olympians. But let’s take a moment here to appreciate and be awed by our ability to command the muscles to move at all. An act as simple as raising a hand, for example, can be lost in motor neuron diseases, which can take one by surprise.
Amyotrophic lateral sclerosis, or ALS, is a progressive neurological disease that causes gradual degeneration and death of motor neurons (nerve cells that control voluntary muscles), leading to an eventual loss of voluntary movements, such as walking, talking, swallowing, and breathing.
Despite being one of the most common neuromuscular diseases worldwide, we don’t really have a clear understanding of what causes ALS.
About 1 in 10 cases of ALS is inherited, or familial. Since the first discovery of a genetic variant linked to ALS in 1993, scientists have unraveled the underlying genetic mutations in about two-thirds of the familial cases. These mutations are found in various genes, ranging from those involved in gene regulation, to protein recycling, to ensuring the proper structures of neurons. “Overall, it is becoming increasingly clear that a number of cellular defects can lead to motor neuron degeneration in ALS,” states National Institute of Neurological Disorders and Stroke (NIHDS).
The majority of the cases, however, seem as if they occur at random, with no genetic predisposition or other associated risk factors. This form of ALS is said to be sporadic.
Researchers all over the world are trying to understand what triggers the selective destruction of motor neurons in ALS. Understanding the cause (the why) and the mechanisms (they how) would help us to come up with effective treatment to halt the degeneration and to eventually cure the disease.
A team of scientists led by Norbert Weiss at the Academy of Sciences of the Czech Republic, Prague, focused their attention on one form of familial ALS in order to gain better understanding of the disease.
In a previous study by the team’s collaborators in the University of Sydney, the genetic screening of a man diagnosed with ALS, with no family history of the disease, led to the identification of two recessive mutations in CACNA1H — a gene that encodes a calcium channel, a protein involved in motor-related activities. The man had inherited one mutation from each parent.
The researchers observed a mild functional effect in each of the variant, which could explain why the parents of the man diagnosed with ALS are not affected by the disease. When the functional changes caused by the two mutations were combined in a computational simulation, the mutations resulted in significant alterations in the channel function, that may be the underlying cause of ALS.
“This study thus provides new fundamental knowledge into the genetic of ALS, and established for the first time CACNA1H as a susceptibility gene in ALS,” Weiss says.
The scientists reported their findings in the journal Channels.
Two recessive variants were identified in the ALS case that the Weiss team investigated. In recessive variants, as opposed to dominant variants, two copies of genetic mutations (each inherited from the mother and the father) are needed to be predisposed to the disease. Having one copy of the variant does not affect the function of the gene, thus the parents are not affected. Because of this, some inherited ALS cases can be misinterpreted as sporadic, the scientists say.
CACNA1H gene encodes a type of calcium channels (T-type voltage-gated calcium channels, or CaV3.2), one of several ion channels that are essential in regulating neuronal activities that send and receive messages to and fro the body.
An ion channel is like a gate that allows for the very finely tuned fluxes of particular ions (in this case calcium ions) in and out of the cells or within cellular compartments.
These flows of ions dictate many important physiological activities in the body, from pumping of the heart, to thinking, to running. As defective gates could become too tight or loose if they are misaligned or missing a hinge, mutations in these channels could disrupt their ability to control the flow of ions, ultimately leading to pathological phenotypes in the functions that they regulate.
When ions pass through channels, miniscule electric current is generated. (Quick physics reminders: ions are charged molecules, and an electric current is a flow of electric charge.) The researchers measured the current passing through the mutated channels and compared their properties against the wild type (carrying no genetic variant).