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Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia.

Nature communications

Authors: 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, 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, Tobias B Haack

Most patients with a rare movement disorder (MD) do not receive a molecular diagnosis, and the underlying genetic variants and mediating genes remain elusive. Here, we evaluate the diagnostic accuracy of conventional and next-generation sequencing-based genetic testing strategies in a cohort of 2,811 individuals with ataxia, spastic paraplegia and dystonia. Exome sequencing establishes genetic diagnoses in 19.3% of cases, and specificity of phenotypic features and age at testing are positive predictors. Genome analysis 'beyond the exome' increases the diagnostic yield by 7.5%, mostly due to the improved detection of structural variants and repeat expansions. Unsolved cases are included in the Solve-RD cohort and subjected to gene-burden analysis, providing evidence for loss-of-function variants in X-chromosomal CD99L2 causing spastic ataxia. Cellular studies show that the transmembrane protein CD99L2 occurs mainly in a ubiquitinated form and serves as an activating interactor of the calcium-dependent protease CAPN1. Ablation of cytoplasmic or extracellular domains of CD99L2 leads to its intracellular mislocalization and abrogation of its interplay with CAPN1. Transcriptome analysis in CD99L2 patient-derived fibroblasts reveals synaptic function-specific disturbances. Impaired CAPN1 activation and dysregulation of downstream neuronal pathways constitute the likely molecular cause for neurodegeneration.

© 2026. The Author(s).

PMID: 41690933

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