The seizures typically begin in the first months of life. It often takes years, however, before those suffering from the rare glucose transporter type 1 (Glut1) deficiency syndrome obtain a correct diagnosis. If the disorder goes untreated, affected children experience developmental delay and frequently have neurological problems.
Various defects in one gene underlie the syndrome. They cause the Glut1 protein to lose its function in the cell membrane: the protein no longer transports glucose from the blood into the brain. The study was published in the current issue of the journal Cell
Miniscule changes in previously little-noticed flexible segments of the Glut1 protein could lead to severe cellular disturbances the same mechanism might cause other genetic disorders.
A fundamental problem
Selbach's team wanted to answer a basic question: Within the Glut1 gene, there are many places where a mutation can disrupt the Glut1 protein's three-dimensional structure, leading to loss of function.
The protein can no longer carry out its task in the cellular machinery and thus triggers the syndrome. The same process is at work in most genetically determined disorders.
But the mechanism involved in genetically determined diseases or, in other words, the cause at the molecular level is often unclear. In one-fifth of all genetic diseases. In such cases, she says, the mutation occurs in flexible loops in the proteins, which until recently were thought to have no function because they lack a defined structure.
These so-called intrinsically disordered regions (IDRs) can snuggle up to other proteins as if they were soft pillows, thereby manipulate them." Many cellular processes are based on such interactions between proteins. The molecules interlock with each other like cogs, transfer energy, or move levers and conveyor belt systems.
Subtle change with a big impact
The doctoral student did this by recreating 258 flexible protein regions in test tubes both "healthy" variants as well as disease-related ones—and then adding human cell extracts. The next step involved using mass spectrometry to determine which proteins interact with the artificial proteins.
In Meyer's experiment, the mutated and "healthy" regions mostly docked onto the same binding partners. Some genetic changes even affect intracellular protein transport through this process. An example is a mutation in the gene for the Glut1 protein that causes two specific building blocks of protein, namely leucines, to lie next to one another, creating a so-called dileucine motif.
Right protein, wrong place
It was a special moment when Meyer made this discovery. If the protein itself is not affected but only the transport function, there is a chance that the underlying cause can be treated not just the symptom. The patient donated cells to her. In tests on cell cultures, Meyer showed that the mutated Glut1 protein was no longer present on the cell surface, where it takes up glucose.
The cellular apparatus involved in pinching off vesicles from the cell membranes and transporting them into the cell's interior via endocytosis is partially responsible for misrouting the Glut1 protein. Meyer was able to confirm her hypothesis: When she blocked this process, the Glut1 protein found its way back to the cell surface and resumed glucose uptake. Medications could theoretically block this.
A new mechanism for numerous diseases
These medications don't exist yet, says Matthias Selbach, head of the laboratory, but the discovery has implications beyond Glut1. By searching databases, the research team found the dileucine motif eleven times in the flexible regions of eight proteins, including in the protein that triggers the metabolic disorder cystic fibrosis.
They have identified a promising target against a wide range of diseases. Future studies will need to determine whether these diseases can be systematically fought with endocytosis blockers.