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Hum Mol Genet. 2018 Feb 15;27(4):706-715. doi: 10.1093/hmg/ddx436.

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

Author information

1
Department of Neurology, Ulm University, 89081 Ulm, Germany.
2
Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland.
3
Molecular Cardiology, Department of Internal Medicine II, Ulm University Medical Center, 89081 Ulm, Germany.
4
Institute for Functional Genomics, University Regensburg, 93053 Regensburg, Germany.
5
Neuromuscular Research Center, Tampere University and University Hospital, 33014 Tampere, Finland.
6
Neurological Department, Helsinki University Hospital, 00029 Helsinki, Finland.
7
Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
8
German Center for Neurodegenerative Diseases, Dresden Research Site, 01307 Dresden, Germany.
9
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany.
10
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
11
Zentrale Einrichtung Elektronenmikroskopie, Universitaet Ulm, 89081 Ulm, Germany.
12
Department of Pharmacology and Clinical Neuroscience, Umeå University, 90187 Umeå, Sweden.
13
Department of Biomedicine, University of Bergen, 5020 Bergen, Norway.

Abstract

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.

PMID:
29315381
DOI:
10.1093/hmg/ddx436
[Indexed for MEDLINE]

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