Scientists have identified the genetic cause of excessive sweating

Rare changes in the SCN10A gene can disrupt the functioning of the sympathetic nervous system and cause primary hyperhidrosis — excessive sweating unrelated to heat or exercise. Experiments on mice have also shown that suppression of the activity of the sodium channel NaV1.8 encoded by this gene reduces sweat production. This was reported on July 17 in the journal Science Advances.

What is hyperhidrosis?

Sweating is necessary for the body to maintain a normal temperature, but with hyperhidrosis, the sweat glands work more actively than they need to cool the body. Most often, the disease affects the palms, feet, armpits, and face. Seizures can occur in a cool room, at rest, or increase due to emotional stress.

This condition can seriously affect daily life. It can be difficult for people to use touch devices, work with papers, wear light clothes, shake hands and be in public places. Patients may experience anxiety and avoid social contact. Experts emphasize that hyperhidrosis cannot be considered an exclusively cosmetic problem.

According to the authors of the new study, primary idiopathic hyperhidrosis can affect from 2 to 5% of the population. At the same time, about two thirds of patients report cases of the disease among their relatives. Despite this prevalence, the specific molecular mechanisms of the hereditary form of the disorder remained unknown for a long time.

How scientists discovered a possible cause of hyperhidrosis

The researchers conducted a complete exome sequencing of participants from 32 families in which increased sweating was observed in representatives of several generations. The work included patients who were not helped by local treatment methods. This suggested that the disorder may be related not only to the sweat glands, but also to the functioning of the nervous system.

The scientists analyzed about 20,000 protein-coding genes, and then identified 13 of the most likely candidates. They paid special attention to the genes of potential-dependent sodium channels. These structures regulate the passage of sodium ions through cell membranes and are involved in the generation of electrical impulses in the nervous system.

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A statistically significant association was found for the SCN10A gene encoding the NaV1 sodium channel.8. Rare variants of this gene were present in six of the 32 examined patients, or in 18.8% of cases. In a control sample of 1,304 people, similar changes were detected in 6.8% of the participants.

These data do not mean that any changes in SCN10A necessarily lead to hyperhidrosis. Rare variants of the gene were also found in people without a diagnosed disease. In addition, the study included a small and specially selected group of families with hereditary hyperhidrosis, which did not respond well to local treatment. The authors talk about the genetic cause of only one of the possible subtypes of the disease.

The experts examined the p.R14L variant in the most detail. It was found in a man who had suffered from severe sweating in the face, head and torso since childhood. Because of his symptoms, he had to change his clothes several times a day and choose mostly dark clothes. A similar disorder was observed in his maternal relatives.

At the same time, the patient's mother also had the p.R14L variant, but she did not notice any signs of hyperhidrosis. This indicates incomplete penetrance: a genetic change may increase the risk of the disease, but it does not necessarily manifest itself in every carrier. The development of symptoms is likely influenced by other genes and external factors.

How does the mutation affect the nervous system

Laboratory experiments have shown that variant p.R14L enhances the activity of NaV1.8. The peak density of electric current in cells with a modified channel turned out to be approximately twice as high as in cells with its usual shape. In addition, the mutated channel was activated at a lower voltage.

This means that nerve cells can more easily switch to an excited state and respond more strongly to incoming signals. Previously, NaV1.8 was primarily associated with pain transmission, but researchers have also found this channel in part of the neurons of the thoracic sympathetic ganglia in humans and mice.

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Its presence in cholinergic postganglionic neurons has become especially important. It is these cells that transmit a signal to the sweat glands using the neurotransmitter acetylcholine. Analysis of intracellular calcium concentrations showed that neurons with variant p.R14L reacted more strongly to carbachol, a substance that mimics the action of acetylcholine.

The obtained results allowed the authors to propose a neurogenic model of the disease. In some patients, the sweat glands themselves may be structurally normal, but they receive excessively strong commands from the sympathetic nervous system. This may explain why topical remedies do not help all people with hyperhidrosis.

What the experiments showed

To test the hypothesis, scientists used CRISPR/Cas9 technology to create mice with the NaV1.8 p.R14L variant. Unlike humans, eccrine sweat glands in mice are concentrated mainly on the pads of the paws. Therefore, the amount of sweat released was determined using an iodine starch test: dark dots appeared in the places where drops appeared.

The males with the mutation had about 49% more sweating area than the animals without the genetic change. In females, the difference reached 50%. Thus, option p.R14L has reproduced one of the key signs of hyperhidrosis in animals.

The mice were then injected with the experimental compound A-887826, which predominantly suppresses NaV1.8. After that, sweating in animals with the mutation decreased by about 70% in males and 69% in females. In mice in which the gene for this channel was completely turned off, sweat production was about a third lower than normal.

The authors also studied the opposite variant of SCN10A — p.C1288W, found in a patient with anhidrosis, i.e. insufficient sweating. It weakened the NaV1 operation.8. Mice with this change secreted 35-37% less sweat than control animals. The combination of two results — increased sweating with increased channel activity and decreased sweating with reduced channel activity — reinforced the assumption of a causal role for NaV1.8.

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However, the genetic picture turned out to be more complicated. The son of the patient with variant p.C1288W, despite the expected decrease in sweating, suffered from hyperhidrosis. Scientists have found an additional change in his AQP5 gene. This gene encodes the protein aquaporin-5, which is involved in the movement of water through the cells of sweat glands. Laboratory experiments have shown that the detected variant increases water permeability and can potentially block the effect of a weakened nerve signal.

Thus, excessive sweating can occur at different levels. In one case, the cause is excessive excitability of sympathetic neurons, in the other, changes in the sweat glands themselves. In some patients, both mechanisms are capable of acting simultaneously.

Limitations of the study

The main limitation of the work is the small number of surveyed families. The genetic relationship was assessed among 32 patients with hereditary hyperhidrosis resistant to local therapy, so the figures obtained cannot be transferred to all people with excessive sweating.

Most of the causal experiments were conducted on cell cultures and genetically modified mice. The location and function of sweat glands in mice and humans differ significantly: mice do not use body-wide sweating to regulate temperature. The created model reproduces individual disease mechanisms, but not the entire human syndrome.

In addition, scientists will have to determine which variants of SCN10A are really pathogenic and in which proportion of patients hyperhidrosis is associated with the nervous system. This will require larger studies, analysis of various populations, and experiments with human neurons derived from induced pluripotent stem cells.

Nevertheless, the work changes the understanding of primary hyperhidrosis. At least in some cases, it can be considered not only as a malfunction of the skin and sweat glands, but also as a disease of the nervous system. In the future, genetic diagnosis can help to divide patients into groups and choose therapy based on the specific mechanism of increased sweating.