A hidden gene finally explains this rare neurological disorder
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- Ruhr University Bochum researchers analyzed 2,811 patients with ataxia, hereditary spastic paraplegia, and dystonia, identifying harmful variants in the CD99L2 gene as the cause of X-linked spastic ataxia.
- CD99L2 was previously recognized only for its role in the immune system, with no established neurological function until the study demonstrated it is essential for nerve-cell communication.
- The CD99L2 protein acts as an activating partner for CAPN1, a calcium-dependent protease already linked to hereditary spastic paraplegia and ataxia; disease-causing variants disrupt CD99L2 production and block its interaction with CAPN1.
- Patients' cells showed specific disruptions of synaptic processes, and reduced CAPN1 activation, providing a likely mechanistic explanation for the movement-related symptoms, according to Dr. Jonasz Weber.
- Dr. Tobias Haack supervised the large-scale genetic analysis in Tübingen, while Weber and colleagues at Ruhr University Bochum's Department of Human Genetics led the functional studies.
- The study, published in Nature Communications, underscores the value of combining genetic diagnostics with functional neuroscience to derive reliable disease mechanisms from genetic variants.
Why it matters: Identifying CD99L2 as a new disease-causing gene gives clinicians a diagnostic target for the many rare movement-disorder patients whose genetic cause remains unknown despite advanced sequencing, while the CD99L2–CAPN1 interaction opens a fresh avenue for understanding how neurodegeneration disrupts neuronal signaling.
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