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

Menden B, Incebacak Eltemur RD, Demidov G, Sturm M, Park J, Huridou C, Fath F, Nümann A, Baumann A, Diets IJ, Dufke C, Regensburger M, Rönnefarth M, Wilke V, van Os N, Vielhaber S, Rattay TW, Kohl Z, Peralta S, Pereira Sena P, Kellner M, Weissert N, Traschütz A, Zeltner L, Boelmans K, Deininger N, Schütz L, Gross C, Hinojosa Amaya AB, Raupach K, Hengel H, Harmuth F, Admard J, Bader I, Baumann S, Bender F, Bevot A, Bischoff A, Boschann F, Buchert R, Buchzik D, Casadei N, Catarino CB, Cordts I, Cremer K, Doebler-Neumann M, Ehmke N, Elbracht M, Falb RJ, Feindt T, Fleszar Z, Gerstner L, Gläser D, Grasshoff U, Grosch S, Grundmann K, Gutschalk A, Haaga M, Hayer S, Hehr U, Hellenbroich Y, Henn W, Herr B, Herzog R, Horber V, Deppe J, Kaiser N, Kehrer C, Kehrer M, Kern J, Keßler C, Khuller K, Klinkhammer H, Kotzaeridou U, Krawitz P, Kreiss M, Küpper H, Kuster A, Laugwitz L, Lesemann A, Lichey N, Linden T, Macek B, Magg J, Mangold E, Manka E, Marquardt I, Mehnert K, Mengel D, Morlot S, Oehl-Jaschkowitz B, Pauly MG, Philipp M, Radelfahr F, Rautenberg M, Riess A, Saft C, Schlotter-Weigel B, Schmidt A, Schwaibold EM, Spahlinger V, Spranger S, Steiner KM, Stendel C, Thieme A, Tzschach A, Velic A, Wiethoff S, Wilke C, Züchner S, Zittel S, Husain RA, Deschauer M, Distelmaier F, Dufke A, Graessner H, Hemmer B, Jacobi H, Klockgether T, Klopstock T, Kobeleva X, Korenke GC, Kuechler A, Kuhlenbäumer G, Kurth I, Nguyen HP, Wunderlich G, Zeuner KE, Klebe S, Auer-Grumbach M, Butryn M, Winkler J, Timmann D, Synofzik M, van de Warrenburg B, Schüle R, Schöls L, Ossowski S, Riess O, Weber JJ, Haack TB (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 17

Pages Range: 1698-

Journal Issue: 1

DOI: 10.1038/s41467-026-69337-9

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.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Tübingen Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Klinikum der Universität München (LMU Klinikum) Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Diakonie-Klinikum Schwäbisch Hall Germany (DE) Technische Universität München (TUM) Germany (DE) Universitätsklinikum Bonn Germany (DE) Universitätsklinikum Aachen (UKA) Germany (DE) Universitätsklinikum Essen Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) Université de Nantes France (FR) Universitätsklinikum Freiburg Germany (DE) Universitätsklinikum Münster Germany (DE) Hertie-Institut für klinische Hirnforschung Germany (DE) University of Miami United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Universitätsklinikum Jena Germany (DE) Universitätsklinikum Düsseldorf Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Carl von Ossietzky Universität Oldenburg Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Ruhr-Universität Bochum (RUB) Germany (DE) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Universitätsklinikum Magdeburg A.ö.R. Germany (DE) Universitätsklinikum Regensburg Germany (DE) Universitätsklinikum Würzburg Germany (DE) genetikum – Genetische Beratung & Diagnostik Germany (DE) Institut für Immunologie und Genetik Germany (DE) Gottfried Wilhelm Leibniz Universität Hannover Germany (DE) Bioscientia MVZ Labor Saar GmbH Germany (DE) Universität zu Lübeck Germany (DE) Katholisches Klinikum Bochum (St. Josef- und St. Elisabeth-Hospital gGmbH) Germany (DE) Vienna General Hospital / Allgemeines Krankenhaus der Stadt Wien (AKH) Austria (AT) Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Germany (DE)

How to cite

APA:

Menden, B., Incebacak Eltemur, R.D., Demidov, G., Sturm, M., Park, J., Huridou, C.,... Haack, T.B. (2026). Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia. Nature Communications, 17(1), 1698-. https://doi.org/10.1038/s41467-026-69337-9

MLA:

Menden, Benita, et al. "Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia." Nature Communications 17.1 (2026): 1698-.

BibTeX: Download