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SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder

Journal article
Authors V. Del Dotto
F. Ullah
I. Di Meo
P. Magini
M. Gusic
A. Maresca
L. Caporali
F. Palombo
F. Tagliavini
E. H. Baugh
Bertil Macao
Zsolt Szilagyi
C. Peron
M. A. Gustafson
K. Khan
C. La Morgia
P. Barboni
M. Carbonelli
M. L. Valentino
R. Liguori
V. Shashi
J. Sullivan
S. Nagaraj
M. El-Dairi
A. Iannaccone
I. Cutcutache
E. Bertini
R. Carrozzo
F. Emma
F. Diomedi-Camassei
C. Zanna
M. Armstrong
M. Page
N. Stong
S. Boesch
R. Kopajtich
S. Wortmann
W. Sperl
E. E. Davis
W. C. Copeland
M. Seri
Maria Falkenberg
H. Prokisch
N. Katsanis
V. Tiranti
T. Pippucci
V. Carelli
Published in Journal of Clinical Investigation
Volume 130
Issue 1
Pages 108-125
ISSN 0021-9738
Publication year 2020
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 108-125
Language en
Keywords DNA-binding protein, mitochondrial transcription factor, d-loop, opa1, gene, replication, deletions, phosphorylation, instability, twinkle, Research & Experimental Medicine
Subject categories Cell and molecular biology


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.

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