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@ARTICLE{Menden:285259,
author = {Menden, Benita and Incebacak Eltemur, Rana D and Demidov,
German and Sturm, Marc and Park, Joohyun and Huridou,
Chrisovalantou and Fath, Florian and Nümann, Astrid and
Baumann, Alexander and Diets, Illja J and Dufke, Claudia and
Regensburger, Martin and Rönnefarth, Maria and Wilke, Vera
and van Os, Nienke and Vielhaber, Stefan and Rattay, Tim and
Kohl, Zacharias and Peralta, Susana and Pereira Sena,
Priscila and Kellner, Melanie and Weissert, Nadine and
Traschuetz, Andreas and Zeltner, Lena and Boelmans, Kai and
Deininger, Natalie and Schütz, Leon and Gross, Caspar and
Hinojosa Amaya, Ana Beatriz and Raupach, Katrin and Hengel,
Holger and Harmuth, Florian and Admard, Jakob and Bader,
Ingrid and Baumann, Sarah and Bender, Friedemann and Bevot,
Andrea and Bischoff, Almut and Boschann, Felix and Buchert,
Rebecca and Buchzik, Daniel and Casadei, Nicolas and
Catarino, Claudia B and Cordts, Isabell and Cremer, Kirsten
and Doebler-Neumann, Marion and Ehmke, Nadja and Elbracht,
Miriam and Falb, Ruth J and Feindt, Thomas and Fleszar,
Zofia and Gerstner, Lea and Gläser, Dieter and Grasshoff,
Ute and Grosch, Sarah and Grundmann, Kathrin and Gutschalk,
Alexander and Haaga, Manja and Hayer, Stefanie and Hehr, Ute
and Hellenbroich, Yorck and Henn, Wolfram and Herr, Barbara
and Herzog, Rebecca and Horber, Veronka and Deppe, Jonas and
Kaiser, Nadja and Kehrer, Christiane and Kehrer, Martin and
Kern, Jan and Keßler, Christoph and Khuller, Katharina and
Klinkhammer, Hannah and Kotzaeridou, Urania and Krawitz,
Peter and Kreiss, Martina and Küpper, Hanna and Kuster,
Alice and Laugwitz, Lucia and Lesemann, Anne and Lichey,
Nadine and Linden, Tobias and Macek, Boris and Magg, Janine
and Mangold, Elisabeth and Manka, Eva and Marquardt, Iris
and Mehnert, Karl and Mengel, David and Morlot, Susanne and
Oehl-Jaschkowitz, Barbara and Pauly, Martje G and Philipp,
Melanie and Radelfahr, Florentine and Rautenberg, Maren and
Riess, Angelika and Saft, Carsten and Schlotter-Weigel,
Beate and Schmidt, Axel and Schwaibold, Eva M C and
Spahlinger, Veronika and Spranger, Stephanie and Steiner,
Katharina Marie and Stendel, Claudia and Thieme, Andreas and
Tzschach, Andreas and Velic, Ana and Wiethoff, Sarah and
Wilke, Carlo and Züchner, Stephan and Zittel, Simone and
Husain, Ralf A and Deschauer, Marcus and Distelmaier, Felix
and Dufke, Andreas and Graessner, Holm and Hemmer, Bernhard
and Jacobi, Heike and Klockgether, Thomas and Klopstock,
Thomas and Kobeleva, Xenia and Korenke, Georg-Christoph and
Kuechler, Alma and Kuhlenbäumer, Gregor and Kurth, Ingo and
Nguyen, Huu Phuc and Wunderlich, Gilbert and Zeuner, Kirsten
E and Klebe, Stephan and Auer-Grumbach, Michaela and Butryn,
Michaela and Winkler, Jürgen and Timmann, Dagmar and
Synofzik, Matthis and van de Warrenburg, Bart and
Schüle-Freyer, Rebecca and Schöls, Ludger and Ossowski,
Stephan and Riess, Olaf and Weber, Jonasz J and Haack,
Tobias B},
collaboration = {consortium, Solve-RD},
othercontributors = {van Os, Nienke and van de Warrenburg, Bart},
title = {{L}oss-of-function variants in the {CAPN}1 activator
{CD}99{L}2 cause {X}-linked spastic ataxia.},
journal = {Nature Communications},
volume = {17},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {DZNE-2026-00201},
pages = {1698},
year = {2026},
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.},
keywords = {Humans / Calpain: metabolism / Calpain: genetics / Muscle
Spasticity: genetics / Muscle Spasticity: diagnosis / Muscle
Spasticity: metabolism / Spinocerebellar Ataxias: genetics /
Spinocerebellar Ataxias: diagnosis / Spinocerebellar
Ataxias: metabolism / Male / Female / 12E7 Antigen: genetics
/ 12E7 Antigen: metabolism / Optic Atrophy: genetics / Optic
Atrophy: diagnosis / Adult / Loss of Function Mutation /
Exome Sequencing / Adolescent / Cohort Studies /
Fibroblasts: metabolism / Child / Middle Aged / Genetic
Testing / Genetic Diseases, X-Linked: genetics / Genetic
Diseases, X-Linked: diagnosis / Young Adult / Intellectual
Disability / Calpain (NLM Chemicals) / CAPN1 protein, human
(NLM Chemicals) / 12E7 Antigen (NLM Chemicals)},
cin = {Clinical Research (Munich) / AG Düzel / AG Gasser / AG
Schöls},
ddc = {500},
cid = {I:(DE-2719)1111015 / I:(DE-2719)5000006 /
I:(DE-2719)1210000 / I:(DE-2719)5000005},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41690933},
doi = {10.1038/s41467-026-69337-9},
url = {https://pub.dzne.de/record/285259},
}
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