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000285259 037__ $$aDZNE-2026-00201
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000285259 1001_ $$aMenden, Benita$$b0
000285259 245__ $$aLoss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia.
000285259 260__ $$a[London]$$bSpringer Nature$$c2026
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000285259 520__ $$aMost 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.
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000285259 650_7 $$0EC 3.4.22.-$$2NLM Chemicals$$aCalpain
000285259 650_7 $$0EC 3.4.22.52$$2NLM Chemicals$$aCAPN1 protein, human
000285259 650_7 $$2NLM Chemicals$$a12E7 Antigen
000285259 650_2 $$2MeSH$$aHumans
000285259 650_2 $$2MeSH$$aCalpain: metabolism
000285259 650_2 $$2MeSH$$aCalpain: genetics
000285259 650_2 $$2MeSH$$aMuscle Spasticity: genetics
000285259 650_2 $$2MeSH$$aMuscle Spasticity: diagnosis
000285259 650_2 $$2MeSH$$aMuscle Spasticity: metabolism
000285259 650_2 $$2MeSH$$aSpinocerebellar Ataxias: genetics
000285259 650_2 $$2MeSH$$aSpinocerebellar Ataxias: diagnosis
000285259 650_2 $$2MeSH$$aSpinocerebellar Ataxias: metabolism
000285259 650_2 $$2MeSH$$aMale
000285259 650_2 $$2MeSH$$aFemale
000285259 650_2 $$2MeSH$$a12E7 Antigen: genetics
000285259 650_2 $$2MeSH$$a12E7 Antigen: metabolism
000285259 650_2 $$2MeSH$$aOptic Atrophy: genetics
000285259 650_2 $$2MeSH$$aOptic Atrophy: diagnosis
000285259 650_2 $$2MeSH$$aAdult
000285259 650_2 $$2MeSH$$aLoss of Function Mutation
000285259 650_2 $$2MeSH$$aExome Sequencing
000285259 650_2 $$2MeSH$$aAdolescent
000285259 650_2 $$2MeSH$$aCohort Studies
000285259 650_2 $$2MeSH$$aFibroblasts: metabolism
000285259 650_2 $$2MeSH$$aChild
000285259 650_2 $$2MeSH$$aMiddle Aged
000285259 650_2 $$2MeSH$$aGenetic Testing
000285259 650_2 $$2MeSH$$aGenetic Diseases, X-Linked: genetics
000285259 650_2 $$2MeSH$$aGenetic Diseases, X-Linked: diagnosis
000285259 650_2 $$2MeSH$$aYoung Adult
000285259 650_2 $$2MeSH$$aIntellectual Disability
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000285259 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-026-69337-9$$gVol. 17, no. 1, p. 1698$$n1$$p1698$$tNature Communications$$v17$$x2041-1723$$y2026
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