SACRAMENTO, Calif.: The saying “cold hands, warm heart” is usually meant metaphorically — but new research from UC Davis School of Medicine and collaborating institutions suggests it has a striking biological parallel.
In a study of TRPM4 ion channel mutations, researchers found that body temperature plays a key role in which tissues are affected. One mutation becomes active only in cooler skin, and another exerts its effects only at the heart’s warmer, core body temperature. Cell type and local chemical signals also play a role.
The findings, published in the Proceedings of the National Academy of Sciences (PNAS), offer a clear explanation for why disease‑causing TRPM4 mutations lead to mutually exclusive conditions.
“This has been a mystery in the field for years,” said Yuhua Tian, first author of the study, and a visiting assistant professor in the Department of Physiology and Membrane Biology. “We now understand that it’s not just the mutation itself that matters, but where in the body the protein is active and under what conditions.”
First author Yuhua Tian, front, and senior author Jie Zheng in the Zheng Lab in Tupper Hall on the UC Davis campus.
What Is TRPM4?
The TRPM4 gene, found on Chromosome 19, provides instructions for making a protein that acts like a gate in the cell membrane.
When calcium levels inside the cell rise, the gate opens, allowing cations (small ions with a positive charge, such as sodium) to flow into the cell. This alters the cell’s electrical state and sends multiple signals to the cell.
This process is important in many organs, including the heart, where electrical signaling plays a major role in maintaining a normal heart rhythm.
In the skin and immune system, this gated activity helps regulate inflammation and cell migration.
A medical mystery
The researchers used confocal fluorescence microscopy to visualize mutation-related changes in the cell membrane.
Doctors and researchers have known for years that some TRPM4 mutations cause inherited heart disorders. These include progressive familial heart block, which alters the normal beating of the heart, and Brugada syndrome, a condition that disrupts the heart’s normal rhythm.
Other TRPM4 mutations cause rare, but severe, skin diseases, including progressive symmetric erythrokeratodermia (PSEK).
Strikingly, however, patients never develop both, even though the mutations increase TRPM4 activity.
“This didn’t make sense under traditional genetic models,” said Jie Zheng, senior author and professor of physiology and membrane biology at UC Davis. “If the same channel is overactive, why doesn’t it affect every tissue the same way?”
What the researchers discovered
The researchers combined electrophysiology, molecular modeling and mouse genetics to examine how disease‑linked TRPM4 mutations respond to calcium, membrane lipids and temperature. By measuring ion channel activity and cell behavior under skin‑like and heart‑like temperature conditions, they uncovered how heat and cold determine where these mutations cause disease.
The research shows that TRPM4 is controlled by a three‑part system:
- Calcium levels inside the cell
- A membrane lipid called PIP2 (phosphatidylinositol 4,5-bisphosphate), which acts as an on-off switch for activity in a cell
- Temperature, which differs between the skin and the internal organs
Together, these factors determine when and where TRPM4 is active.
Why Temperature Matters
Skin disease mutations break TRPM4’s control by PIP2, allowing the channel to stay active at cooler skin temperatures (25 to 30°C or 77 to 86°F). Extremities like hands and feet, where skin diseases like PSEK can strike, generally have lower temperatures than core body temperature.
The channel loses its abnormal activity at normal body‑core temperature (37°C or 98.6°F).
By comparison, heart disease mutations increase the number of TRPM4 channels in heart cells and boost electrical signaling — but only at body‑core temperature (37°C or 98.6°F). The heart disease mutations were largely inactive in cooler skin tissue.
“This explains why skin mutations cause damage only in the skin, and heart mutations affect only the heart,” Zheng said. “The channel is responding to its environment.”
Clinical Implications
Samuel Hwang, professor and chair of the Department of Dermatology at UC Davis Health, is a co‑author of the study. Hwang treats people with inherited skin conditions in his clinic, but has never seen a case of PSEK. “It is a very rare disease. And the good news is that people often outgrow it after puberty.” He notes the findings could reshape how doctors think about genetic diseases, including skin diseases.
“This work shows that a mutation’s effects depend on tissue context, not just DNA sequence,” Hwang said. “That insight helps explain why some patients develop skin disease without heart involvement, and it suggests new strategies for treating these conditions more precisely.”
Future applications
Zheng emphasized that the results came from an interdisciplinary collaboration among clinicians, biophysicists, computational biologists and dermatologists.
“We hope these findings help clinicians find better treatment strategies for patients and that they give pharmaceutical companies strategies that may lead to new treatments for people with these inherited conditions,” Zheng said.
