SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder
| Autor: | Holger Prokisch, Evan H. Baugh, Valentina Del Dotto, Michele Carbonelli, Rocco Liguori, Mirjana Gusic, Wolfgang Sperl, Tommaso Pippucci, Nicholas Stong, Pamela Magini, Enrico Bertini, William C. Copeland, Alessandra Maresca, Francesca Diomedi-Camassei, Shashi K. Nagaraj, Ioana Cutcutache, Bertil Macao, Alessandro Iannaccone, Francesco Emma, Piero Barboni, Marco Seri, Vandana Shashi, Zsolt Szilagyi, Farid Ullah, Camille Peron, Valerio Carelli, Chiara La Morgia, Ivano Di Meo, Martin Armstrong, Jennifer A. Sullivan, Saskia B. Wortmann, Nicholas Katsanis, Leonardo Caporali, Kamal Khan, Maria Falkenberg, Valeria Tiranti, Mays A. El-Dairi, Erica E. Davis, Maria Lucia Valentino, Margaret A. Gustafson, Claudia Zanna, Rosalba Carrozzo, Sylvia Boesch, Flavia Palombo, Francesca Tagliavini, Robert Kopajtich, Matthew Page |
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| Přispěvatelé: | Del Dotto, Valentina, Ullah, Farid, Di Meo, Ivano, Magini, Pamela, Gusic, Mirjana, Maresca, Alessandra, Caporali, Leonardo, Palombo, Flavia, Tagliavini, Francesca, Baugh, Evan Harri, Macao, Bertil, Szilagyi, Zsolt, Peron, Camille, Gustafson, Margaret A, Khan, Kamal, La Morgia, Chiara, Barboni, Piero, Carbonelli, Michele, Valentino, Maria Lucia, Liguori, Rocco, Shashi, Vandana, Sullivan, Jennifer, Nagaraj, Shashi, El-Dairi, May, Iannaccone, Alessandro, Cutcutache, Ioana, Bertini, Enrico, Carrozzo, Rosalba, Emma, Francesco, Diomedi-Camassei, Francesca, Zanna, Claudia, Armstrong, Martin, Page, Matthew, Stong, Nichola, Boesch, Sylvia, Kopajtich, Robert, Wortmann, Saskia, Sperl, Wolfgang, Davis, Erica E, Copeland, William C, Seri, Marco, Falkenberg, Maria, Prokisch, Holger, Katsanis, Nichola, Tiranti, Valeria, Pippucci, Tommaso, Carelli, Valerio |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mitochondrial DNA Bioenergetic Genetic disease Mitochondrion Biology medicine.disease_cause DNA Mitochondrial Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine Atrophy Mitochondrial myopathy Genetic medicine Humans Mutation Bioenergetics Genetic Diseases Genetics Mitochondria Ophthalmology Optic Nerve General Medicine medicine.disease Molecular biology Hereditary Optic Atrophy Transplantation DNA-Binding Proteins Optic Atrophy 030104 developmental biology 030220 oncology & carcinogenesis Mitochondrial DNA replication Research Article |
| Zdroj: | J. Clin. Invest. 130, 108-125 (2020) |
| Popis: | Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex vivo in biopsies of affected tissues, such as kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology. |
| Databáze: | OpenAIRE |
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