Work by Jawdat Al-Bassam, left, associate professor of molecular and cellular biology at UC Davis and his former student Aryan Taheri (right), now pursuing a Ph.D. at UC Berkeley, has uncovered the root cause of some severe, life-shortening inherited diseases in children.
Photo Credit: Courtesy of University of California, Davis
Scientific Frontline: Extended "At a Glance" Summary: Chaperone Tubulinopathies
The Core Concept: Chaperone tubulinopathies are severe, life-shortening inherited genetic disorders caused by mutations in tubulin cofactors, which are essential proteins that control the formation of a cell's microtubule skeleton. These mutations disrupt the structural development of growing neurons, leading to severe neurological and developmental defects in infants.
Key Distinction/Mechanism: Unlike broader developmental delays, these diseases stem directly from a malfunctioning "spring-and-latch" mechanism within the tubulin cofactor cage. This malfunction reduces the cellular supply of αβ-tubulin dimers, directly impeding the growth of microtubules (the cell's cytoskeleton) necessary to form neuronal axons and connect brain hemispheres and organ systems.
Major Frameworks/Components:
- Microtubules: Telescoping protein structures that act as a cell's skeleton and force generators, driving changes in cell shape and axonal growth.
- αβ-tubulin Dimers: The core building blocks of microtubules, formed by snapping together α-tubulin and β-tubulin proteins.
- Tubulin Cofactors (Chaperone Proteins): A complex protein cage that captures β-tubulin and facilitates its binding with α-tubulin to create essential dimers.
- Cryo-Electron Microscopy (Cryo-EM): The advanced imaging technology utilized to freeze and map the cofactor machine in at least nine different structural configurations.
Branch of Science: Molecular Biology, Cellular Biology, Neurobiology, and Genetics
Future Application: Mapping this molecular machine provides a precise structural target for future gene therapies. Furthermore, identifying specific tubulin cofactor mutations will enable faster, more accurate genetic diagnostics for infants with unexplained neurological conditions, reducing reliance on inconclusive genomic sequencing.
Why It Matters: These disorders—such as infantile encephalopathy, corpus callosum hypoplasia, and Kenny-Caffey syndrome—currently have no treatments. Unlocking the structural mechanics of the responsible protein complex establishes the critical foundation necessary to develop life-saving interventions and uncover additional under-the-radar genetic diseases.
Thousands of times per year, a family’s moment of joy turns to unexpected grief. A seemingly healthy infant stops smiling or making eye contact. Their limbs grow weak. The tiny child suffers seizures and breathing problems.
Jawdat Al-Bassam, an associate professor of molecular and cellular biology at the University of California, Davis, often hears from these families. “I’ve gotten emails from folks all over the world,” he said.
By the time they contact him, they’ve undergone a bewildering medical journey lasting months or years—and received devastating news: their child has a rare genetic disorder called a chaperone tubulinopathy.
“The parents are asking if there’s a way to do gene therapy,” Al-Bassam said. These life-shortening diseases, with names like infantile encephalopathy, corpus callosum hypoplasia, and Kenny-Caffey syndrome, currently have no treatments. But Al-Bassam and his team have made a major discovery that could change that.
In two scientific papers—one published May 8 and the other in December 2025—they have mapped the structure and mechanics of a critical cellular machine that malfunctions in people with these diseases.
In addition to enabling new treatments, this discovery could help scientists identify dozens of other genetic diseases in which children experience various neurological problems with no clear explanation.
Cellular Skeletons Guide Neural Connections
Al-Bassam studies structures called microtubules, which form protein skeletons inside cells. As a cell grows and changes shape, its cytoskeleton drives the process—lengthening its scaffold of microtubules.
“They are the cell’s force generators,” Al-Bassam said. These telescoping structures are crucial in the developing nervous system.
They help nerve cells grow the long tendrils, called axons, that connect with other nerve cells. These axons allow neurons to communicate across long distances—especially in the optic nerves that connect the eyes to the brain, in the corpus callosum that connects the left and right hemispheres of the brain, and in the long nerves that reach down to the arms, legs, lungs, and other organs.
For a baby to develop normal vision, cognition, coordination, and breathing, the neurons have to connect properly. The microtubules must form perfectly inside the growing neurons.
The cell builds microtubules from two proteins, α-tubulin and β-tubulin. Before they can be used, they have to be snapped together into thousands of αβ-tubulin “dimers”—forming the building blocks that can then assemble into microtubules.
Cells control the formation of microtubules, in part, by controlling the supply of the αβ-tubulin dimers. Special “chaperone” proteins—called “tubulin cofactors”—perform this delicate process. As soon as a cell produces a β-tubulin protein, these cofactors assemble into a cage that holds onto the β-tubulin until it can find an α-tubulin and snap them together into an αβ heterodimer, which it then releases.
But this process can easily go awry, with terrible consequences.
If the tubulin cofactors malfunction, it reduces the cell’s supply of αβ-tubulin, disrupting the microtubules that guide neuronal growth. “Even a small percent decrease in αβ-tubulin supply is toxic to the cell,” Al-Bassam said.
Devastating Disorders of Unknown Origins
Scientists have discovered that some children with severe, unexplained neurologic disorders actually have mutations in their tubulin cofactor genes. This may reduce the supply of αβ-tubulin—leading to an underdeveloped corpus callosum, optic nerves, and other brain structures.
“Some of these mutants were identified almost 35 years ago in yeast,” Al-Bassam said. They were discovered 15 years later in humans. But the delicate proteins were difficult to study, he said, “so this whole field of research was essentially shelved for a long time.”
The UC Davis team has now broken that impasse. Using cryo-electron microscopy (cryo-EM), they found how these proteins assemble into a complex machine. Their initial results, published in December 2025 in Nature Communications, show the elegant spring-and-latch mechanism that it uses to capture β-tubulin, snap it onto α-tubulin, and release the αβ dimer. “This was a surprise,” Al-Bassam said. “It was really beautiful.”
These experiments were led by Aryan Taheri, a former UC Davis undergraduate who was working in Al-Bassam’s lab at the time; Taheri has since graduated and is now pursuing a PhD at UC Berkeley. “He’s extremely talented,” Al-Bassam said. “We look forward to seeing more amazing work from him in the future.”
In the second paper published in Science Advances, Al-Bassam and Taheri unveil additional cryo-EM structures, showing the machine frozen in at least nine different configurations. These snapshots reveal how it functions in a complex cycle, snapping together αβ dimers when they are needed and pulling them apart when they aren’t.
These discoveries won’t immediately lead to treatments, but they could offer hope to affected families, Al-Bassam said: “For the first time, we have a precise picture of exactly what’s going wrong and what a future therapy would need to fix.”
They could also allow disorders to be diagnosed more quickly. Today, families often endure a diagnostic odyssey in which the genomes of parent and child are sequenced in search of a mutation that might explain the problem—often yielding inconclusive results. A clearer understanding of which mutations disrupt the function of tubulin cofactors could lead to quicker diagnoses.
This new knowledge might even spur the discovery of other genetic disorders still flying under the radar.
“Many children are born with minor, unexplained neurologic disorders,” Al-Bassam said. “Some of them may turn out to have small changes in these genes. Finding that out would be a huge step forward.”
Funding: Al-Bassam’s research is funded by the National Institutes of Health. His team’s research on αβ-tubulin biogenesis utilized advanced scientific facilities at UC Davis, including the Biological Electron Microscopy Campus Core and the High Performance Computing Core.
Published in journal: Science Advances
Title: A unified mechanism for tubulin cofactors catalyzing α/β-tubulin biogenesis and degradation
Authors: Aryan Taheri, Md Ashaduzzaman, Vishv Gill, Julian A. Eskin, and Jawdat Al-Bassam
Source/Credit: University of California, Davis | Douglas Fox
Reference Number: mbio051026_01
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