Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia

  • Ann Neurol. 2021 Nov;90(5):738-750. doi: 10.1002/ana.26228.
Claudia Schob  1 ,  Maja Hempel  1 ,  Dana Safka Brozkova  2 ,  Huafang Jiang  3 ,  Soo Yeon Kim  4 ,  Nurit Assia Batzir  5 ,  Naama Orenstein  5 ,  Tatjana Bierhals  1 ,  Jessika Johannsen  6 ,  Anna Uhrova Meszarosova  2 ,  Jong-Hee Chae  4  7 ,  Pavel Seeman  2 ,  Mathias Woidy  6 ,  Fang Fang  3 ,  Christian Kubisch  1 ,  Stefan Kindler  1 ,  Jonas Denecke  6
Affiliations
  • 1. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 2. Neurogenetic Laboratory, Department of Pediatric Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.
  • 3. Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
  • 4. Department of Genomics Medicine, Rare Disease Center, Seoul National University Hospital, Seoul, Republic of Korea.
  • 5. Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petah-Tikva, Israel.
  • 6. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 7. Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
PMID: 34564892 DOI: 10.1002/ana.26228
Abstract

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.