Journal
ANNALS OF NEUROLOGY
Volume 90, Issue 5, Pages 738-750Publisher
WILEY
DOI: 10.1002/ana.26228
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Funding
- Deutsche Forschungsgemeinschaft [SPP1935, SCHO 1921/2-1]
- Ministry of Health of the Czech Republic [DRO00064203]
- European Joint Program on Rare Diseases [MEYS 8F20002]
- European Union's Horizon 2020 research and innovation program (EJP RD COFUND-EJP) [825575]
- Projekt DEAL
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The study identified heterozygous variants in KPNA3 as the genetic basis for pure infantile-onset hereditary spastic paraplegia. Mutant karyopherin-alpha 3 proteins exhibit varying deficits in molecular and cellular functions.
Objective Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation. Methods Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. Results Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-alpha 3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. Interpretation Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-alpha 3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021
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