TY - JOUR AU - Piro-Mégy, Camille AU - Sarzi, Emmanuelle AU - Tarrés-Solé, Aleix AU - Péquignot, Marie AU - Hensen, Fenna AU - Quilès, Mélanie AU - Manes, Gaël AU - Chakraborty, Arka AU - Sénéchal, Audrey AU - Bocquet, Béatrice AU - Cazevieille, Chantal AU - Roubertie, Agathe AU - Müller, Agnès AU - Charif, Majida AU - Goudenège, David AU - Lenaers, Guy AU - Wilhelm, Helmut AU - Kellner, Ulrich AU - Weisschuh, Nicole AU - Wissinger, Bernd AU - Zanlonghi, Xavier AU - Hamel, Christian AU - Spelbrink, Johannes N. AU - Sola, Maria AU - Delettre, Cécile T1 - Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy PY - 2020/01/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI128513 VL - 130 IS - 1 UR - https://doi.org/10.1172/JCI128513 SP - 143 EP - 156 PB - The American Society for Clinical Investigation ER -