Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
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
PubMed
34564892
DOI
10.1002/ana.26228
Knihovny.cz E-resources
- MeSH
- alpha Karyopherins genetics MeSH
- Adult MeSH
- Phenotype MeSH
- Heterozygote MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Mutation genetics MeSH
- Child, Preschool MeSH
- Pedigree MeSH
- Exome Sequencing methods MeSH
- Spastic Paraplegia, Hereditary genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- alpha Karyopherins MeSH
- KPNA3 protein, human MeSH Browser
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.
Department of Pediatrics Seoul National University College of Medicine Seoul Republic of Korea
Department of Pediatrics University Medical Center Hamburg Eppendorf Hamburg Germany
Institute of Human Genetics University Medical Center Hamburg Eppendorf Hamburg Germany
Pediatric Genetics Clinic Schneider Children's Medical Center of Israel Petah Tikva Israel
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