Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F21%3A10432315" target="_blank" >RIV/00064203:_____/21:10432315 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11130/21:10432315
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=v~LQm1P5KY" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=v~LQm1P5KY</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/ana.26228" target="_blank" >10.1002/ana.26228</a>
Alternative languages
Result language
angličtina
Original language name
Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia
Original language description
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. This article is protected by copyright. All rights reserved.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30103 - Neurosciences (including psychophysiology)
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Annals of Neurology
ISSN
0364-5134
e-ISSN
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Volume of the periodical
90
Issue of the periodical within the volume
5
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
738-750
UT code for WoS article
000707185100001
EID of the result in the Scopus database
2-s2.0-85116998335