SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder

• DOI: 10.1172/jci128514
• Publication Date: 2019-09-24T16:02:20Z
• Authors: Valentina Del Dotto; Farid Ullah; Ivano Di Meo; Pamela Magini; Mirjana Gusic; Alessandra Maresca; Leonardo Caporali; Flavia Palombo; Francesca Tagliavini; Evan Harris Baugh; Bertil Macao; Zsolt Szilagyi; Camille Peron; Margaret A. Gusta...; Kamal Khan; Chiara La Morgia; Piero Barboni; Michele Carbonelli; Maria Lucia Valen...; Rocco Liguori; Vandana Shashi; Jennifer Sullivan; Shashi Nagaraj; Mays El-Dairi; Alessandro Iannac...; Ioana Cutcutache; Enrico Bertini; Rosalba Carrozzo; Francesco Emma; Francesca Diomedi...; Claudia Zanna; Martin Armstrong; Matthew Page; Nicholas Stong; Sylvia Boesch; Robert Kopajtich; Saskia Wortmann; Wolfgang Sperl; Erica E. Davis; William C. Copeland; Marco Seri; Maria Falkenberg; Holger Prokisch; Nicholas Katsanis; Valeria Tiranti; Tommaso Pippucci; Valerio Carelli
• Keywords: Mitochondrial disease; Heteroplasmy

Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the single-strand binding protein (SSBP1) in 4 families dominant 1 recessive inheritance. show that SSBP1 patient-derived fibroblasts variably affect amount alter multimer formation, but not ssDNA. impaired mtDNA, nucleoids, 7S-DNA amounts as well mtDNA replication, replisome machinery. The variable cells was reflected severity dysfunction, respiratory efficiency, OXPHOS subunits, assembly. cytochrome c oxidase-negative were found ex vivo biopsies affected tissues, such skeletal muscle. Reduced efficiency replication also reproduced vitro, confirming pathogenic mechanism. Furthermore, ssbp1 suppression zebrafish induced signs nephropathy reduced nerve size, latter phenotype complemented WT mRNA mutant transcripts. This previously unrecognized disease maintenance implicates a cause human pathology.