2. Academic Validation
  3. Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia

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

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.

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