Nature communications · 2026

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

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

Аннотация

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.

Предметные рубрики MeSH

Humans Calpain Spinocerebellar Ataxias Male Muscle Spasticity Female Intellectual Disability 12E7 Antigen Fibroblasts Exome Sequencing Genetic Diseases, X-Linked High-Throughput Nucleotide Sequencing Optic Atrophy

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

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Аннотация

Предметные рубрики MeSH