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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2026-02-14
DOI
https://doi.org/10.1038/s41467-026-69337-9
Primary Topic
Hereditary Neurological Disorders
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Manja Haaga, Ana Velić, Georg-Christoph Korenke, Michaela Auer‐Grumbach et al.
Nature Communications
Hereditary Neurological Disorders
article

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

Manja Haaga, Ana Velić, Georg-Christoph Korenke, Michaela Auer‐Grumbach, Leon Schütz, Marcus Deschauer, Peter Michael Krawitz, Jonasz Jeremiasz Weber, Jonas Deppe, Veronika Spahlinger, Tobias Linden, Katharina Khuller, Chrisovalantou Huridou, Angelika Rieß, Stefan Vielhaber, Yorck Hellenbroich, Melanie Philipp, Thomas Feindt, Eva Manka, Jan Marco Kern, Katharina M. Steiner, Priscila Pereira Sena, Astrid Nümann, David Mengel, Stephanie Spranger, Caspar Groß, Nicolas Casadei, Tim W. Rattay, Zofia Fleszar, Maria Rönnefarth, Lucia Laugwitz, Barbara Herr, Maren Rautenberg, Xenia Kobeleva, Kathrin Grundmann, B. Oehl-Jaschkowitz, L. Schöls, Anne Lesemann, Martin Kehrer, Elisabeth Mangold, Andreas Traschütz, Nienke J.H. van Os, Andreas Gustafsson Thieme, Melanie Kellner, Martje G. Pauly, Felix Boschann, U Hehr, Lena Zeltner, Michaela Butryn, Nadine Lichey, Vera Wilke, Isabell Cordts, Florian Fath, Ute Grasshoff, Susanne Morlot, Friedemann Bender, Martina Kreiß, Janine Magg, Illja J. Diets, Christiane Kehrer, Marion Doebler-Neumann, Dagmar Timmann, H. Küpper, Sarah Grosch, Sarah Baumann, Nadine Weissert, Joohyun Park, Susana Peralta, Rebecca Herzog, Saft Carsten, H. P. Nguyen, Stephan Klebe, Alice Küster, Marc Sturm, Iris Marquardt, Kirsten E. Zeuner, Carlo Wilke, Kirsten Cremer, Dieter Gläser, Katrin Raupach, Urania Kotzaeridou, Daniel Buchzik, Ingo Kurth, Ralf A Husain, Beate Schlotter-Weigel, Jürgen Winkler, Holm Graessner, Heike Jacobi, Rebecca Buchert, Alma Kuechler, T Klopstock, Andrea Bevot, Veronka Horber, Gilbert Wunderlich, German Demidov, Almut T. Bischoff, M. Regensburger, T. B. Haack, H. Hengel, Rana D. Incebacak Eltemur, Alexander Baumann, Christoph Keßler, Ruth J. Falb, Ingrid Bader, Alexander Gutschalk, Axel Schmidt, Eva M. C. Schwaibold, Florian Harmuth, Nadja Kaiser, Felix Distelmaier, Zacharias Kohl, Karl Mehnert, Florentine Radelfahr, Benita Menden, Hannah Klinkhammer, Bart van de Warrenburg, Stephan Züchner, Natalie Deininger, Claudia B. Catarino, Nadja Ehmke, Lea Gerstner, Stephan Ossowski, Wolfram Henn, Andreas Dufke, Bernhard Hemmer, Thomas Klockgether, Jakob Admard, Claudia Stendel, Kai Boelmans, Olaf Riess, Ana Beatriz Hinojosa Amaya, Boris Macek, Gregor Kuhlenbäumer, Claudia Dufke
article en

Abstract

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.

Nature CommunicationsVol. 17(1)
Leibniz University Hannover (DE), Carl von Ossietzky Universität Oldenburg (DE), University of Bonn (DE), Radboud University Nijmegen (NL), University of Kaiserslautern (DE), Universität Hamburg (DE), University of Cologne (DE), Heidelberg University (DE), University Hospital Bonn (DE), Africa Center (US), University Hospitals of the Ruhr-University of Bochum (DE), University Medical Center Freiburg (DE), German Center for Neurodegenerative Diseases (DE), University Hospital Heidelberg (DE), Vienna General Hospital (AT), Radboud University Medical Center (NL), University Hospital Regensburg (DE), Christian-Albrechts-Universität zu Kiel (DE), Humboldt-Universität zu Berlin (DE), Universitätsklinikum Erlangen (DE), Düsseldorf University Hospital (DE), University Hospital Münster (DE), Genetikum (DE), Klinikum Magdeburg (DE), University Medical Center Hamburg-Eppendorf (DE), Klinikum Oldenburg (DE), University Hospital Schleswig-Holstein (DE), Munich Cluster for Systems Neurology (DE), Praxis für Humangenetik Tübingen (DE), Knappschaftskrankenhaus Recklinghausen (DE), Essen University Hospital (DE), Universitätsklinikum Aachen (DE), University Children's Hospital Tübingen (DE), Universitätsklinikum Würzburg (DE), Dr. John T. Macdonald Foundation (US), Friedrich Baur Stiftung (DE), Jena University Hospital (DE), Praxis für Humangenetik (DE), University Hospital Magdeburg (DE), St. Josef-Hospital (DE), Klinikum Bremerhaven-Reinkenheide (DE), Hertie Institute for Clinical Brain Research (DE), Evangelisches Diakoniekrankenhaus (DE), Center for Genomic Science (IT), University Hospital Cologne (DE), Heinrich Heine University Düsseldorf (DE), University of Duisburg-Essen (DE), Technical University of Munich (DE), University of Applied Sciences Kaiserslautern (DE), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), RWTH Aachen University (DE), Ruhr University Bochum (DE), University of Lübeck (DE), Nantes Université (FR)
Good health and well-being
Openalex Percentile: Top 57%
Hereditary Neurological Disorders
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.