ArticleNature communications2026
Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia.
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1 citing paper in PubMed.
- Advancing the diagnosis of rare neuromuscular and neurological diseases through the collaborative Solve-RD research framework.Journal of neuromuscular diseases · 2026Review
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142 authors.
Benita Menden *Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Rana D Incebacak Eltemur *Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-2522-6562
German DemidovInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-9075-4276
Marc SturmInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-6552-8362
Joohyun ParkInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Chrisovalantou HuridouInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-1796-8240
Florian FathInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Astrid NümannDepartment of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Alexander BaumannDepartment of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.
Illja J DietsDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
Claudia DufkeInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-5225-2443
Martin RegensburgerDepartment of Molecular Neurology, University Hospital Erlangen, Erlangen, Germany.ORCID http://orcid.org/0000-0002-2172-7386
Maria RönnefarthDepartment of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Vera WilkeDepartment of Neurology and Center for rare diseases, University Hospital Tübingen, Tübingen, Germany.
Nienke van OsDepartment of Neurology, Radboud University medical center, Nijmegen, Netherlands.
Stefan VielhaberDepartment of Neurology, University Hospital Magdeburg, Magdeburg, Germany.
Tim W RattayDepartment of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.ORCID http://orcid.org/0000-0002-5456-7761
Zacharias KohlDepartment of Neurology, University Hospital Regensburg, Regensburg, Germany.
Susana PeraltaInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-4406-0617
Priscila Pereira SenaInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-2061-5470
Melanie KellnerDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Nadine WeissertDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Andreas TraschützDivision Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University Hospital Tübingen, Tübingen, Germany.
Lena ZeltnerDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Kai BoelmansDepartment of Neurology, University Hospital Würzburg, Würzburg, Germany.
Natalie DeiningerInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Leon SchützInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-7907-4878
Caspar GrossInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-9009-5458
Ana Beatriz Hinojosa AmayaInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-9439-7368
Katrin RaupachInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Holger HengelDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-9773-2667
Florian HarmuthInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Jakob AdmardInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0003-0466-582X
Ingrid BaderInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Sarah BaumannInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Friedemann BenderDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Andrea BevotDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Almut BischoffFriedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, Ludwig-Maximilian University (LMU) Munich, Munich, Germany.
Felix BoschannInstitute of Human Genetics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Rebecca BuchertInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-7576-3326
Daniel BuchzikSozialpädiatrisches Zentrum, Diakoneo Diak Klinikum Schwäbisch Hall, Schwäbisch Hall, Germany.
Nicolas CasadeiInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0003-2209-0580
Claudia B CatarinoFriedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, Ludwig-Maximilian University (LMU) Munich, Munich, Germany.ORCID http://orcid.org/0000-0002-6528-7570
Isabell CordtsDepartment of Neurology, Technical University Munich, Munich, Germany.
Kirsten CremerInstitute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany.
Marion Doebler-NeumannDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Nadja EhmkeInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0003-1449-9909
Miriam ElbrachtCenter for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen, Aachen, Germany.ORCID http://orcid.org/0000-0001-5088-1369
Ruth J FalbInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Thomas FeindtPraxis Neurologie Magdeburg, Magdeburg, Germany.
Zofia FleszarDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Lea GerstnerInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-9525-1288
Dieter Gläsergenetikum, Neu-Ulm, Germany.
Ute GrasshoffInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Sarah GroschInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Kathrin GrundmannInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Alexander GutschalkDepartment of Neurology, University Hospital Heidelberg, Heidelberg, Germany.ORCID http://orcid.org/0000-0002-2523-8846
Manja HaagaDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Stefanie HayerDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Ute HehrZentrum für Humangenetik Regensburg, Regensburg, Germany.
Yorck HellenbroichDepartment of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany.
Wolfram HennInstitute of Immunology and Genetics, Practice for human genetics in the Medicushaus Kaiserslautern, Kaiserslautern, Germany.
Barbara HerrInstitute of Human Genetics, University Hospital Freiburg, Freiburg, Germany.
Rebecca HerzogDepartment of Neurology, University Hospital Lübeck, Lübeck, Germany.
Veronka HorberDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Jonas DeppeDepartment of Neurology, Technical University Munich, Munich, Germany.
Nadja KaiserDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Christiane KehrerDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Martin KehrerInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Jan KernDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-8526-3894
Christoph KeßlerDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Katharina KhullerInstitute of Human Genetics, University Hospital Essen, Essen, Germany.
Hannah KlinkhammerInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0003-3752-1275
Urania KotzaeridouDepartment of Pediatrics, University of Heidelberg, Heidelberg, Germany.
Peter KrawitzInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-3194-8625
Martina KreissInstitute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany.
Hanna KüpperDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Alice KusterDepartment of Pediatrics, University of Nantes, Nantes, France.ORCID http://orcid.org/0000-0002-1365-6354
Lucia LaugwitzDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0003-2506-1961
Anne LesemannDepartment of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Nadine LicheyPraxis für Humangenetik, Bremen, Germany.
Tobias LindenDepartment of Pediatrics, University of Oldenburg, Oldenburg, Germany.
Boris MacekProteome Center Tübingen, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-1206-2458
Janine MaggDepartment of Neuropediatrics, General Pediatrics, Endocrinology, Diabetology, Social Pediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Elisabeth MangoldInstitute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-3819-2576
Eva MankaDepartment of Pediatrics, University Hospital Essen, Essen, Germany.
Iris MarquardtDepartment of Pediatrics, University of Oldenburg, Oldenburg, Germany.
Karl Mehnertgenetikum, Neu-Ulm, Germany.
David MengelDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Susanne MorlotInstitute of Human Genetics, University of Hannover, Hannover, Germany.
Barbara Oehl-JaschkowitzMVZ Labor Saar GmbH, Praxis für Humangenetik, Homburg, Germany.
Martje G PaulyInstitute of Systems Motor Science, University of Lübeck, Lübeck, Germany.ORCID http://orcid.org/0000-0002-7794-0282
Melanie PhilippDepartment of Experimental and Clinical Pharmacology and Pharmacogenomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0003-2714-965X
Florentine RadelfahrFriedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, Ludwig-Maximilian University (LMU) Munich, Munich, Germany.
Maren RautenbergInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Angelika RiessInstitute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany.
Carsten SaftDepartment of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
Beate Schlotter-WeigelFriedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, Ludwig-Maximilian University (LMU) Munich, Munich, Germany.
Axel SchmidtInstitute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-9780-7243
Eva M C SchwaiboldInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.ORCID http://orcid.org/0000-0003-2708-9642
Veronika SpahlingerDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Stephanie SprangerPraxis für Humangenetik, Bremen, Germany.
Katharina Marie SteinerDepartment of Neurology, University Hospital Essen, Essen, Germany.
Claudia StendelFriedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, Ludwig-Maximilian University (LMU) Munich, Munich, Germany.
Andreas ThiemeDepartment of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0001-6221-8601
Andreas TzschachInstitute of Human Genetics, University Hospital Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0002-6840-965X
Ana VelicProteome Center Tübingen, University of Tübingen, Tübingen, Germany.
Sarah WiethoffDepartment of Neurology, University Hospital Münster, Münster, Germany.
Carlo WilkeDivision Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University Hospital Tübingen, Tübingen, Germany.
Stephan ZüchnerDepartment of Human Genetics and John P. Hussman Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, USA.ORCID http://orcid.org/0000-0002-8498-5235
Simone ZittelDepartment of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.ORCID http://orcid.org/0000-0002-3767-6376
Solve-RD consortium
Ralf A HusainDepartment of Neuropediatrics, Jena University Hospital, Jena, Germany.ORCID http://orcid.org/0000-0003-0798-6346
Marcus DeschauerDepartment of Neurology, Technical University Munich, Munich, Germany.
Felix DistelmaierDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.ORCID http://orcid.org/0000-0003-4304-7848
Andreas DufkeInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-5616-5010
Holm GraessnerInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-9803-7183
Bernhard HemmerDepartment of Neurology, Technical University Munich, Munich, Germany.ORCID http://orcid.org/0000-0001-5985-6784
Heike JacobiDepartment of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
Thomas KlockgetherDepartment of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0001-6174-5442
Thomas KlopstockFriedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, Ludwig-Maximilian University (LMU) Munich, Munich, Germany.ORCID http://orcid.org/0000-0003-2805-4652
Xenia KobelevaDepartment of Neurology, University of Bonn, Medical Faculty & University Hospital Bonn, Bonn, Germany.
Georg-Christoph KorenkeDepartment of Pediatrics, University of Oldenburg, Oldenburg, Germany.
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, Essen, Germany.
Gregor KuhlenbäumerDepartment of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.ORCID http://orcid.org/0000-0002-3262-8113
Ingo KurthCenter for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen, Aachen, Germany.ORCID http://orcid.org/0000-0002-5642-8378
Huu Phuc NguyenDepartment of Human Genetics, Ruhr University Bochum, Bochum, Germany.ORCID http://orcid.org/0000-0001-6139-788X
Gilbert WunderlichDepartment of Neurology and Center for Rare Diseases, University of Cologne, Faculty of Medicine and University Hospital, Köln, Germany.ORCID http://orcid.org/0000-0001-5544-335X
Kirsten E ZeunerDepartment of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany.
Stephan KlebeDepartment of Neurology, University Hospital Essen, Essen, Germany.
Michaela Auer-GrumbachDepartment of Orthopedics and Trauma-Surgery, University Hospital Vienna, Vienna, Austria.
Michaela ButrynDeutsches Zentrum für Neurodegenerative Erkrankungen Magdeburg, Magdeburg, Germany.
Jürgen WinklerDepartment of Molecular Neurology, University Hospital Erlangen, Erlangen, Germany.ORCID http://orcid.org/0000-0003-0630-9204
Dagmar TimmannDepartment of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Matthis SynofzikDivision Translational Genomics of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University Hospital Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-2280-7273
Bart van de WarrenburgDepartment of Neurology, Radboud University medical center, Nijmegen, Netherlands.
Rebecca SchüleHertie Institute for Clinical Brain Research and Center of Neurology, University Hospital Tübingen, Tübingen, Germany.
Ludger SchölsDepartment of Neurology, University Hospital Tübingen, Tübingen, Germany.
Stephan OssowskiInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-7416-9568
Olaf RiessInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-7011-1369
Jonasz J WeberInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. jonaszjeremiasz.weber@rub.de.ORCID http://orcid.org/0000-0003-3758-1569
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. tobias.haack@med.uni-tuebingen.de.ORCID http://orcid.org/0000-0001-6033-4836
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
12E7 AntigenCalpainGenetic Diseases, X-LinkedIntellectual DisabilityMuscle SpasticitySpinocerebellar AtaxiasExome SequencingFemaleFibroblastsHigh-Throughput Nucleotide SequencingHumansMaleOptic Atrophy12E7 AntigenCalpainCAPN1 protein, human
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