An immune-related gene has now been tied to a rare inherited neurological disorder, revealing an overlooked pathway in the nervous system.
Even with today’s high-throughput sequencing tools, many rare movement disorders still do not have a clear genetic explanation. A study from researchers in Bochum and Tübingen now points to one more answer.
After analyzing 2,811 people with ataxia, hereditary spastic paraplegia, and dystonia, the team identified disease-causing variants in the gene CD99L2 as the cause of X-linked spastic ataxia. The study was published in Nature Communications.
Spastic ataxia is a group of rare neurodegenerative disorders that combine two major problems: impaired coordination and muscle stiffness or spastic paralysis. These symptoms can develop when disease affects both the cerebellum, which helps control balance and coordination, and the motor pathways of the central nervous system. The age at which symptoms begin, and how quickly they progress, can vary depending on the underlying genetic cause.
A gene with a previously unknown neurological function
Until now, CD99L2 was mainly associated with the immune system, with no known function in the nervous system. Using a combination of genome-wide analysis and cell-based experiments, the researchers demonstrated that this gene plays an important role in neuronal signaling pathways.
The Bochum team found that the protein produced by CD99L2 serves as an activating partner for CAPN1, a calcium-dependent protease already linked to 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.”
Lower CAPN1 activity, along with the resulting disruption of neuronal signaling, offers a clear explanation for the symptoms seen in affected individuals.
Linking Genetic Diagnostics and Functional Neuroscience
“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.”
Identifying CD99L2 as a disease-related gene not only strengthens genetic testing for rare movement disorders but also deepens understanding of the biological processes that drive neurodegeneration.
Reference: “Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia” by Benita Menden, Rana D. Incebacak Eltemur, German Demidov, Marc Sturm, Joohyun Park, Chrisovalantou Huridou, Florian Fath, Astrid Nümann, Alexander Baumann, Illja J. Diets, Claudia Dufke, Martin Regensburger, Maria Rönnefarth, Vera Wilke, Nienke van Os, Stefan Vielhaber, Tim W. Rattay, Zacharias Kohl, Susana Peralta, Priscila Pereira Sena, Melanie Kellner, Nadine Weissert, Andreas Traschütz, Lena Zeltner, Kai Boelmans, Natalie Deininger, Leon Schütz, Caspar Gross, Ana Beatriz Hinojosa Amaya, Katrin Raupach, Holger Hengel, Florian Harmuth, Jakob Admard, Ingrid Bader, Sarah Baumann, Friedemann Bender, Andrea Bevot, Almut Bischoff, Felix Boschann, Rebecca Buchert, Daniel Buchzik, Nicolas Casadei, Claudia B. Catarino, Isabell Cordts, Kirsten Cremer, Marion Doebler-Neumann, Nadja Ehmke, Miriam Elbracht, Ruth J. Falb, Thomas Feindt, Zofia Fleszar, Lea Gerstner, Dieter Gläser, Ute Grasshoff, Sarah Grosch, Kathrin Grundmann, Alexander Gutschalk, Manja Haaga, Stefanie Hayer, Ute Hehr, Yorck Hellenbroich, Wolfram Henn, Barbara Herr, Rebecca Herzog, Veronka Horber, Jonas Deppe, Nadja Kaiser, Christiane Kehrer, Martin Kehrer, Jan Kern, Christoph Keßler, Katharina Khuller, Hannah Klinkhammer, Urania Kotzaeridou, Peter Krawitz, Martina Kreiss, Hanna Küpper, Alice Kuster, Lucia Laugwitz, Anne Lesemann, Nadine Lichey, Tobias Linden, Boris Macek, Janine Magg, Elisabeth Mangold, Eva Manka, Iris Marquardt, Karl Mehnert, David Mengel, Susanne Morlot, Barbara Oehl-Jaschkowitz, Martje G. Pauly, Melanie Philipp, Florentine Radelfahr, Maren Rautenberg, Angelika Riess, Carsten Saft, Beate Schlotter-Weigel, Axel Schmidt, Eva M. C. Schwaibold, Veronika Spahlinger, Stephanie Spranger, Katharina Marie Steiner, Claudia Stendel, Andreas Thieme, Andreas Tzschach, Ana Velic, Sarah Wiethoff, Carlo Wilke, Stephan Züchner, Simone Zittel, Solve-RD consortium, Ralf A. Husain, Marcus Deschauer, Felix Distelmaier, Andreas Dufke, Holm Graessner, Bernhard Hemmer, Heike Jacobi, Thomas Klockgether, Thomas Klopstock, Xenia Kobeleva, Georg-Christoph Korenke, Alma Kuechler, Gregor Kuhlenbäumer, Ingo Kurth, Huu Phuc Nguyen, Gilbert Wunderlich, Kirsten E. Zeuner, Stephan Klebe, Michaela Auer-Grumbach, Michaela Butryn, Jürgen Winkler, Dagmar Timmann, Matthis Synofzik, Bart van de Warrenburg, Rebecca Schüle, Ludger Schöls, Stephan Ossowski, Olaf Riess, Jonasz J. Weber and Tobias B. Haack, 14 February 2026, Nature Communications.
DOI: 10.1038/s41467-026-69337-9
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.