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SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder
Valentina Del Dotto, … , Tommaso Pippucci, Valerio Carelli
Valentina Del Dotto, … , Tommaso Pippucci, Valerio Carelli
Published September 24, 2019
Citation Information: J Clin Invest. 2020;130(1):108-125. https://doi.org/10.1172/JCI128514.
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Research Article Genetics Ophthalmology

SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder

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Abstract

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.

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. Gustafson, Kamal Khan, Chiara La Morgia, Piero Barboni, Michele Carbonelli, Maria Lucia Valentino, Rocco Liguori, Vandana Shashi, Jennifer Sullivan, Shashi Nagaraj, Mays El-Dairi, Alessandro Iannaccone, Ioana Cutcutache, Enrico Bertini, Rosalba Carrozzo, Francesco Emma, Francesca Diomedi-Camassei, 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

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Figure 3

Ophthalmologic phenotype associated with the p.G40V SSBP1 mutation.

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Ophthalmologic phenotype associated with the p.G40V SSBP1 mutation.
In a...
In all panels, the right eye (OD) is illustrated as representative of both eyes. Disease expression in this proband ascertained at Duke (PT3) was symmetric. (A) Ophthalmoscopy showed diffuse optic nerve pallor and blunted foveal reflexes, but enhanced vitreoretinal interface reflexes and marked vasculature attenuation with ghost vessel–like appearance. (B) RNFL OCT scan obtained at the age of 17 years, 10 months: the average RNFL thickness was only approximately 60–65 μm in each eye. (C) At age 23 years, there was no significant change in the extent of the RNFL loss. (D) The macular OCT obtained at the age of 17 years, 10 months, shows mild thinning of all retinal layers and marked loss of the EZ (red arrows), with foveal sparing and presence of subfoveal hyperreflectivity at the EZ/RPE interface (white arrow). (E) Followup macular OCT at age 23 years showed significant increase in the thinning of all retinal layers and further contraction of EZ residue (red arrows), but persistent subfoveal hyperreflectivity (white arrow). Hyporeflective cystic spaces consistent with macular edema had developed at this age as well (white asterisk) Scale bars 200 µm.
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