Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia

Ann Neurol. 2021 Nov;90(5):738-750. doi: 10.1002/ana.26228. Epub 2021 Oct 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child, Preschool
  • Exome Sequencing / methods
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Spastic Paraplegia, Hereditary / genetics*
  • Young Adult
  • alpha Karyopherins / genetics*


  • KPNA3 protein, human
  • alpha Karyopherins