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| Home > In process > Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia. |
| Home > In process > Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia. |
| Journal Article | DZNE-2026-00201 |
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2026
Springer Nature
[London]
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Please use a persistent id in citations: 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.
Keyword(s): Humans (MeSH) ; Calpain: metabolism (MeSH) ; Calpain: genetics (MeSH) ; Muscle Spasticity: genetics (MeSH) ; Muscle Spasticity: diagnosis (MeSH) ; Muscle Spasticity: metabolism (MeSH) ; Spinocerebellar Ataxias: genetics (MeSH) ; Spinocerebellar Ataxias: diagnosis (MeSH) ; Spinocerebellar Ataxias: metabolism (MeSH) ; Male (MeSH) ; Female (MeSH) ; 12E7 Antigen: genetics (MeSH) ; 12E7 Antigen: metabolism (MeSH) ; Optic Atrophy: genetics (MeSH) ; Optic Atrophy: diagnosis (MeSH) ; Adult (MeSH) ; Loss of Function Mutation (MeSH) ; Exome Sequencing (MeSH) ; Adolescent (MeSH) ; Cohort Studies (MeSH) ; Fibroblasts: metabolism (MeSH) ; Child (MeSH) ; Middle Aged (MeSH) ; Genetic Testing (MeSH) ; Genetic Diseases, X-Linked: genetics (MeSH) ; Genetic Diseases, X-Linked: diagnosis (MeSH) ; Young Adult (MeSH) ; Intellectual Disability (MeSH) ; Calpain ; CAPN1 protein, human ; 12E7 Antigen
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