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Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia

C. Schob, M. Hempel, D. Safka Brozkova, H. Jiang, SY. Kim, NA. Batzir, N. Orenstein, T. Bierhals, J. Johannsen, A. Uhrova Meszarosova, JH. Chae, P. Seeman, M. Woidy, F. Fang, C. Kubisch, S. Kindler, J. Denecke

. 2021 ; 90 (5) : 738-750. [pub] 20211014

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22003262

Grant support
SCHO 1921/2-1 Deutsche Forschungsgemeinschaft
SPP1935 Deutsche Forschungsgemeinschaft
MEYS 8F20002 European Joint Programme on Rare Diseases
EJP RD COFUND-EJP N° 825575 European Union's Horizon 2020 research and innovation programme
DRO00064203 Ministerstvo Zdravotnictví Ceské Republiky
Seoul National University

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-α3 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-α3 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;90:738-750.

References provided by Crossref.org

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