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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3496-3514
Number of pages19
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

Keywords

  • Dominant Optic Atrophy (DOA)
  • Mitochondrial functions
  • Mitochondrial network
  • mtDNA
  • OPA1
  • OPA1 mutations

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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