Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F19%3A10395503" target="_blank" >RIV/00064203:_____/19:10395503 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11130/19:10395503

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=zba_1vuFur" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=zba_1vuFur</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/hmg/ddz006" target="_blank" >10.1093/hmg/ddz006</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations

Popis výsledku v původním jazyce

Mutations in MORC2 lead to an axonal form of Charcot-Marie-Tooth (CMT) neuropathy type 2Z. To date, 31 families have been described with mutations in MORC2, indicating that this gene is frequently involved in axonal CMT cases. While the genetic data clearly establish the causative role of MORC2 in CMT2Z, the impact of its mutations on neuronal biology and their phenotypic consequences in patients remains to be clarified. We show that the full-length form of MORC2 is highly expressed in both embryonic and adult human neural tissues and that Morc2 expression is dynamically regulated in both the developing and the maturing murine nervous system. To determine the effect of the most common MORC2 mutations, p.S87L and p.R252W, we used several in vitro cell culture paradigms. Both mutations induced transcriptional changes in patient-derived fibroblasts and when expressed in rodent sensory neurons. These changes were more pronounced and accompanied by abnormal axonal morphology, in neurons expressing the MORC2 p.S87L mutation, which is associated with a more severe clinical phenotype. These data provide insight into the neuronal specificity of the mutated MORC2-mediated phenotype and highlight the importance of neuronal cell models to study the pathophysiology of CMT2Z. (C) The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Název v anglickém jazyce

Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations

Popis výsledku anglicky

Mutations in MORC2 lead to an axonal form of Charcot-Marie-Tooth (CMT) neuropathy type 2Z. To date, 31 families have been described with mutations in MORC2, indicating that this gene is frequently involved in axonal CMT cases. While the genetic data clearly establish the causative role of MORC2 in CMT2Z, the impact of its mutations on neuronal biology and their phenotypic consequences in patients remains to be clarified. We show that the full-length form of MORC2 is highly expressed in both embryonic and adult human neural tissues and that Morc2 expression is dynamically regulated in both the developing and the maturing murine nervous system. To determine the effect of the most common MORC2 mutations, p.S87L and p.R252W, we used several in vitro cell culture paradigms. Both mutations induced transcriptional changes in patient-derived fibroblasts and when expressed in rodent sensory neurons. These changes were more pronounced and accompanied by abnormal axonal morphology, in neurons expressing the MORC2 p.S87L mutation, which is associated with a more severe clinical phenotype. These data provide insight into the neuronal specificity of the mutated MORC2-mediated phenotype and highlight the importance of neuronal cell models to study the pathophysiology of CMT2Z. (C) The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/NV16-30206A" target="_blank" >NV16-30206A: Celogenomové a RNA masivně paralelní sekvenování jako nástroj pro objasnění příčin vzácných typů dědičných neuropatií.</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

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

Název periodika

Human Molecular Genetics

ISSN

0964-6906

e-ISSN

—

Svazek periodika

28

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

16

Strana od-do

1629-1644

Kód UT WoS článku

000475882600005

EID výsledku v databázi Scopus

2-s2.0-85068493842