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Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models

Del Dotto, Valentina and Fogazza, Mario and Musiani, Francesco and Maresca, Alessandra and Aleo, Serena J. and Caporali, Leonardo and La Morgia, Chiara and Nolli, Cecilia and Lodi, Tiziana and Goffrini, Paola and Chan, David and Carelli, Valerio and Rugulo, Michela and Baruffini, Enrico and Zanna, Claudia (2018) Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864 (10). pp. 3496-3514. ISSN 0925-4439. doi:10.1016/j.bbadis.2018.08.004.

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OPA1 is the major gene responsible for Dominant Optic Atrophy (DOA) and the syndromic form DOA “plus”. Over 370 OPA1 mutations have been identified so far, although their pathogenicity is not always clear. We have analyzed one novel and a set of known OPA1 mutations to investigate their impact on protein functions in primary skin fibroblasts and in two “ad hoc” generated cell systems: the MGM1/OPA1 chimera yeast model and the Opa1−/− MEFs model expressing the mutated human OPA1 isoform 1. The yeast model allowed us to confirm the deleterious effects of these mutations and to gain information on their dominance/recessivity. The MEFs model enhanced the phenotypic alteration caused by mutations, nicely correlating with the clinical severity observed in patients, and suggested that the DOA “plus” phenotype could be induced by the combinatorial effect of mitochondrial network fragmentation with variable degrees of mtDNA depletion. Overall, the two models proved to be valuable tools to functionally assess and define the deleterious mechanism and the pathogenicity of novel OPA1 mutations, and useful to testing new therapeutic interventions.

Item Type:Article
Related URLs:
URLURL TypeDescription
Maresca, Alessandra0000-0002-8959-8832
Chan, David0000-0002-0191-2154
Additional Information:© 2018 Elsevier. Received 12 January 2018, Revised 24 July 2018, Accepted 1 August 2018, Available online 4 August 2018. This work was supported by the Futuro in Ricerca FIR2013 from the Ministero della Istruzione Università e Ricerca (MIUR) [RBFR131WDS-001 to CZ and RBFR131WDS-002 to EB]; and the National Institutes of Health [GM110039 to DCC]. We thank Mirca Lazzaretti for the helpful technical assistance with the fluorescence microscope in yeast. The authors declare no financial conflict of interest that might be construed to influence the results or interpretation of the manuscript. Authors contributions: Conceptualization, VDD, EB and CZ; Methodology, VDD, EB and CZ; Investigation, VDD, MF, FM, AM, SJA, LC, CLM, CN, EB and CZ; Resources, DC; Writing – Original Draft, VDD, EB and CZ; Writing – Review & Editing, VDD, TL, PG, DC, VC, MR, EB and CZ; Visualization, VDD, EB and CZ; Funding Acquisition, DC and CZ; Supervision, MR, TL, PG, EB and CZ; Project Administration, EB and CZ.
Funding AgencyGrant Number
Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR)RBFR131WDS-001
Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR)RBFR131WDS-002
Subject Keywords:OPA1 mutations; Dominant Optic Atrophy (DOA); OPA1; Mitochondrial network; mtDNA; Mitochondrial functions
Issue or Number:10
Record Number:CaltechAUTHORS:20180806-125015141
Persistent URL:
Official Citation:Valentina Del Dotto, Mario Fogazza, Francesco Musiani, Alessandra Maresca, Serena J. Aleo, Leonardo Caporali, Chiara La Morgia, Cecilia Nolli, Tiziana Lodi, Paola Goffrini, David Chan, Valerio Carelli, Michela Rugolo, Enrico Baruffini, Claudia Zanna, Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 10, 2018, Pages 3496-3514, ISSN 0925-4439, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:88601
Deposited By: George Porter
Deposited On:06 Aug 2018 23:24
Last Modified:16 Nov 2021 00:28

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