Human Genetics

New Genetic Cause of Rare Movement Disorder Discovered

Despite modern high-throughput sequencing, the genetic cause of most rare movement disorders remains unclear. A research team in Bochum and Tübingen has now solved one piece of the puzzle: The researchers examined 2,811 patients with ataxia, hereditary spastic paraplegia, and dystonia and identified disease-causing variants of the gene CD99L2 as the cause of X-linked spastic ataxia. The findings were published in Nature Communications on February 14, 2026.

A gene with a previously unknown neurological function

CD99L2 was primarily known for its functions in the immune system, but no role in the nervous system had previously been described. Only by combining genome-wide analysis with cellular biological experiments were the researchers able to show that the gene plays a key role in neuronal signal pathways.

The researchers in Bochum demonstrated that the protein coded by CD99L2 acts as an activating partner for the calcium-dependent protease CAPN1, a known disease protein in spastic paraplegia and ataxia. “Disease-causing variants lead to disrupted production of the CD99L2 protein in the cell and prevent its interaction with CAPN1,” explains Dr. Jonasz Weber. “Patients’ cells also showed specific disruptions of synaptic processes.” The reduced CAPN1 activation and the resulting dysregulation of neuronal signal pathways plausibly explain the observed symptoms.

“Our results show that genetic diagnostics and functional neuroscience are not mutually exclusive areas,” says Weber. “Only when both disciplines work closely together can a reliable disease mechanism be derived from a genetic variant.”

The identification of CD99L2 as a new disease gene not only improves genetic diagnostics for rare movement disorders, but also provides new insights into fundamental neurodegenerative mechanisms.