Abstrakt
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 eight patients with a uniform clinical presentation.
METHODS: Trio whole exome sequencing was utilized in five index patients with infantile onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified utilizing bioinformatics and complementary cellular and biochemical assays.
RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in eight patients, in four of them KPNA3 variants have occurred de novo. Mutant Karyopherin-α3 proteins exhibit 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.
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