Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11130/21:10432315

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Dominant KPNA3 Mutations Cause Infantile Onset Hereditary Spastic Paraplegia

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Annals of Neurology

ISSN

0364-5134

e-ISSN

—

Svazek periodika

90

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

738-750

Kód UT WoS článku

000707185100001

EID výsledku v databázi Scopus

2-s2.0-85116998335