Credit: Wikimedia Commons
When six infants around the world were diagnosed with an odd trio of symptoms (diabetes, epilepsy, and abnormally small heads) scientists suspected a hidden genetic thread. Now, after years of detective work, researchers from the University of Exeter and the Université Libre de Bruxelles have uncovered the culprit: a single gene called TMEM167A.
Their study, published in The Journal of Clinical Investigation, reveals that mutations in TMEM167A cause a rare condition known as microcephaly, epilepsy, and diabetes syndrome (MEDS). It’s a devastating disease that strikes in the first months of life, shutting down insulin-producing cells and impairing brain development.
“Finding the DNA changes that cause diabetes in babies gives us a unique way to find the genes that play key roles in making and secreting insulin,” said Dr. Elisa De Franco of the University of Exeter, who co-led the study with diabetologist Miriam Cnop of the Free University of Brussels. “The finding of specific DNA changes causing this rare type of diabetes in six children led us to clarifying the function of a little-known gene, TMEM167A, showing how it plays a key role in insulin secretion.”
Genetic Detectives
The researchers performed whole-genome sequencing on six infants diagnosed before six months of age. All shared the same haunting clinical picture: diabetes, severe microcephaly, and (in five of the six) epilepsy. These children came from unrelated families scattered across continents. Yet, they carried mutations in both copies of the TMEM167A gene, inherited from each parent.
Until now, scientists had identified only two genes that could cause meds: IER3IP1 and YIPF5. They now know a third in the form of TMEM167A. All three genes, it turns out, perform vital roles in a part of the cell called the endoplasmic reticulum (ER). It is a labyrinthine factory where proteins like insulin are folded, packaged, and sent out.
When TMEM167A malfunctions, that factory grinds to a halt. In pancreatic beta cells, which produce insulin, this failure leads to a toxic buildup of misfolded proteins, triggering a stress response that ultimately kills the cell.
“The ability to generate insulin-producing cells from stem cells has enabled us to study what is dysfunctional in the beta cells of patients with rare forms as well as other types of diabetes,” said Professor Miriam Cnop. “This is an extraordinary model for studying disease mechanisms and testing treatments.”
What the Experiments Revealed
To understand how TMEM167A works, Cnop’s team turned to CRISPR, a powerful gene-editing tool often described as molecular “scissors.” CRISPR allows researchers to cut and modify DNA with remarkable precision. The scientists used CRISPR to recreate one of the patient mutations in human stem cells, then coaxed those cells to develop into pancreatic beta cells, the body’s insulin factories.
At first glance, the engineered cells looked perfectly normal. But when exposed to glucose, something crucial was missing: they failed to release insulin.
Inside the cells, things were far from normal. The beta cells showed clear signs of ER stress, a kind of cellular distress also seen in type 2 diabetes, where overworked beta cells begin to malfunction and die.
The researchers also found that TMEM167A is highly active in both the pancreas and the brain. That dual activity explains why mutations in the same gene can lead to insulin failure as well as neurological symptoms such as epilepsy and microcephaly.
In embryos, TMEM167A is expressed in the developing brain’s neural progenitor cells, the ancestors of neurons. Without it, these cells may fail to form normal brain structures, leading to microcephaly and, in some cases, lissencephaly—a rare condition in which the brain surface appears unusually smooth.
In their experiments, the team also observed mitochondrial dysfunction and disrupted electrical signaling in cells carrying the mutation. Even when implanted into mice, these altered beta cells produced almost no human insulin.
Looking Ahead
There’s no clear cure for this problem at the moment. But for the families affected, this discovery offers some clarity and hope. Knowing the exact genetic cause helps doctors provide more accurate diagnoses and genetic counseling. It may also guide research toward new treatments aimed at easing cellular stress in diabetes.
Cnop’s team found that certain experimental drugs helped protect the mutant beta cells from stress-induced death in the lab. These findings suggest that the ER stress response might one day become a therapeutic target for diabetes, both rare and common.
In a way, the infants with mutated cells may help rewrite what we know about one of humanity’s most common diseases.