Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy

Piro-Megy Camille, Sarzi Emmanuelle, Tarrés-Solé Aleix, Péquignot Marie, Hensen Fenna, Quilès Mélanie, Manes Gael, Chakraborty Arka, Sénéchal Audrey, Bocquet Béatrice, Cazevieille Chantal, Roubertie Agathe, Müller Agnès, Charif Majida, Goudenège David, Lenaers Guy, Wilhelm Helmut, Kellner Ulrich, Weisschuh Nicole, Wissinger Bernd, Zanlonghi Xavier, Hamel Christian P., Spelbrink Johannes N., Sola Maria, Delettre Cécile. 2020. Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy. Journal of Clinical Investigation, 130 (1) : 143-156.

Quartile : Outlier, Sujet : MEDICINE, RESEARCH & EXPERIMENTAL

Résumé : Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders.

Mots-clés Agrovoc : mutation, atrophie, adn mitochondrial, adn, fibroblaste, variation génétique, protéine, identification, phylogénie, polymorphisme génétique

Auteurs et affiliations

• Piro-Megy Camille, Université de Montpellier (FRA) ORCID: 0009-0007-1275-2612 - auteur correspondant
• Sarzi Emmanuelle, INSERM (FRA) - auteur correspondant
• Tarrés-Solé Aleix, IBMB-CSIC (ESP)
• Péquignot Marie, INSERM (FRA)
• Hensen Fenna, Radboud Center for Mitochondrial Medicine (NLD)
• Quilès Mélanie, INSERM (FRA)
• Manes Gael, Université de Montpellier (FRA)
• Chakraborty Arka, IBMB-CSIC (ESP)
• Sénéchal Audrey, INSERM (FRA)
• Bocquet Béatrice, Université de Montpellier (FRA)
• Cazevieille Chantal, Université de Montpellier (FRA)
• Roubertie Agathe, Université de Montpellier (FRA)
• Müller Agnès, INSERM (FRA)
• Charif Majida, Université de Montpellier (FRA)
• Goudenège David, Université d'Angers (FRA)
• Lenaers Guy, INSERM (FRA)
• Wilhelm Helmut, University of Tübingen (DEU)
• Kellner Ulrich, Rare Retinal Disease Center (DEU)
• Weisschuh Nicole, University of Tübingen (DEU)
• Wissinger Bernd, University of Tübingen (DEU)
• Zanlonghi Xavier, Clinique Pluridisciplinaire Jules Verne (FRA)
• Hamel Christian P., INSERM (FRA)
• Spelbrink Johannes N., Radboud Center for Mitochondrial Medicine (NLD)
• Sola Maria, IBMB-CSIC (ESP)
• Delettre Cécile, INSERM (FRA)

Source : Cirad-Agritrop (https://agritrop.cirad.fr/611329/)

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