Cover Image

CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency

Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p.R15L and p.G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p.P34S in vitro, in patient cells as well as in the vertebrate in...

Full description

Saved in:
Bibliographic Details
Main Authors: Brockmann, Sarah J. (Author) , Freischmidt, Axel (Author) , Oeckl, Patrick (Author) , Müller, Kathrin (Author) , Ponna, Srinivas K (Author) , Helferich, Anika Marie (Author) , Paone, Christoph (Author) , Reinders, Jörg (Author) , Kojer, Kerstin (Author) , Orth, Michael (Author) , Jokela, Manu (Author) , Auranen, Mari (Author) , Udd, Bjarne (Author) , Hermann, Andreas (Author) , Danzer, Karin M (Author) , Lichtner, Peter (Author) , Walther, Paul (Author) , Ludolph, Albert C. (Author) , Andersen, Peter M (Author) , Otto, Markus (Author) , Kursula, Petri (Author) , Just, Steffen (Author) , Weishaupt, Jochen H. (Author)
Format: Article (Journal)
Language:English
Published: 05 January 2018
In: Human molecular genetics
Year: 2018, Volume: 27, Issue: 4, Pages: 706-715
ISSN:1460-2083
DOI:10.1093/hmg/ddx436
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/hmg/ddx436
Get full text
Author Notes:Sarah J. Brockmann, Axel Freischmidt, Patrick Oeckl, Kathrin Müller, Srinivas K. Ponna, Anika M. Helferich, Christoph Paone, Jörg Reinders, Kerstin Kojer, Michael Orth, Manu Jokela, Mari Auranen, Bjarne Udd, Andreas Hermann, Karin M. Danzer, Peter Lichtner, Paul Walther, Albert C. Ludolph, Peter M. Andersen, Markus Otto, Petri Kursula, Steffen Just and Jochen H. Weishaupt
Description
Summary:Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p.R15L and p.G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p.P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p.R15L and p.G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p.R15L, but not of CHCHD10 p.G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p.G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p.P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.
Item Description:Gesehen am 08.07.2021
Physical Description:Online Resource
ISSN:1460-2083
DOI:10.1093/hmg/ddx436

Similar Items