Researchers Identify CD99L2 Mutations as a Cause of Rare Inherited Spastic Ataxia
Scientists have identified mutations in a little-known gene called CD99L2 as the cause of a rare inherited form of spastic ataxia, providing an explanation for a neurological disorder that had previously remained undiagnosed in some patients despite extensive genetic testing.
The findings reveal a previously unknown role for CD99L2 in the nervous system and show how changes in this gene disrupt communication between nerve cells. The research also suggests that including CD99L2 in genetic testing panels could improve the diagnosis of rare inherited movement disorders.
Researchers Linked CD99L2 to a Rare Neurological Disorder
The research team analyzed DNA from 2,811 individuals diagnosed with ataxia, hereditary spastic paraplegia, or dystonia. Using genome-wide sequencing alongside laboratory experiments, the researchers identified harmful variants in CD99L2 that were consistently associated with a distinct neurodegenerative disorder affecting movement.
Before this study, CD99L2 was known primarily for its role in immune function and blood vessel biology. Although genetic variants had occasionally been identified during sequencing, there was little evidence that the gene played an important role in the nervous system.
The new findings demonstrate that CD99L2 is essential for normal signaling within neurons. Patient-derived cells carrying disease-causing variants showed impaired cellular communication, indicating that the gene is necessary for maintaining healthy nerve cell function.
How CD99L2 Mutations Affect the Brain
Researchers at Ruhr University Bochum discovered that the CD99L2 protein acts as an activator of CAPN1, a calcium-dependent protease previously linked to hereditary spastic paraplegia and certain forms of ataxia. CAPN1 helps regulate proteins involved in synaptic function, the process by which neurons communicate with one another.
According to the researchers, disease-causing CD99L2 variants interfere with normal production of the protein and prevent it from interacting effectively with CAPN1. Reduced activation of CAPN1 disrupts normal synaptic signaling, ultimately contributing to the movement problems observed in affected individuals.
Combining Genetics With Laboratory Validation
The researchers emphasize that identifying potentially harmful genetic variants is only the first step in diagnosing rare diseases. Laboratory studies are often necessary to determine whether newly discovered variants actually alter cellular function and cause disease.
By confirming CD99L2 as a disease-causing gene, the study provides clinicians with a new target for genetic testing in patients with unexplained ataxia or hereditary spastic paraplegia. Earlier and more accurate diagnosis may improve genetic counseling, support family planning decisions, and facilitate participation in future clinical trials aimed at treating the underlying biological mechanisms.
Understanding Spastic Ataxia
Spastic ataxia describes a group of neurological disorders characterized by both impaired coordination and increased muscle stiffness. Damage affecting the cerebellum and long motor pathways can lead to an unsteady gait, balance problems, muscle spasticity, and progressive difficulty with movement.
Symptoms may begin during childhood or adulthood depending on the specific genetic cause. Identifying genes such as CD99L2 helps distinguish different forms of these rare disorders, improve diagnostic accuracy, refine prognosis, and support the development of more targeted treatment strategies.
The large-scale genetic analysis was coordinated in Tübingen under the leadership of Dr. Tobias Haack, while the laboratory experiments investigating CD99L2 function were led by Dr. Jonasz Weber and colleagues at Ruhr University Bochum. Together, the findings provide new insight into the biological mechanisms underlying inherited movement disorders and open new avenues for research into neurodegenerative diseases.
