Brockmann, Sarah J. and Freischmidt, Axel and Oeckl, Patrick and Mueller, Kathrin and Ponna, Srinivas K. and Helferich, Anika M. and Paone, Christoph and Reinders, Joerg and Kojer, Kerstin and Orth, Michael and Jokela, Manu and Auranen, Mari and Udd, Bjarne and Hermann, Andreas and Danzer, Karin M. and Lichtner, Peter and Walther, Paul and Ludolph, Albert C. and Andersen, Peter M. and Otto, Markus and Kursula, Petri and Just, Steffen and Weishaupt, Jochen H. (2018) CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency. HUMAN MOLECULAR GENETICS, 27 (4). pp. 706-715. ISSN 0964-6906, 1460-2083
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MOTOR-NEURON DISEASE; GENE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Mar 2020 09:04 |
| Last Modified: | 18 Mar 2020 09:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15038 |
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