SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder PMID: 31550240

ADC Targets in Oncology

2026-04-10

SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder

J Clin Invest. 2020 Jan 2;130(1):108-125. doi: 10.1172/JCI128514.

Valentina Del Dotto ¹ , Farid Ullah ² ³ ⁴ , Ivano Di Meo ⁵ , Pamela Magini ⁶ , Mirjana Gusic ⁷ ⁸ , Alessandra Maresca ⁹ , Leonardo Caporali ⁹ , Flavia Palombo ⁹ , Francesca Tagliavini ⁹ , Evan Harris Baugh ¹⁰ , Bertil Macao ¹¹ , Zsolt Szilagyi ¹¹ , Camille Peron ⁵ , Margaret A Gustafson ¹² , Kamal Khan ² ³ ⁴ , Chiara La Morgia ¹ ⁹ , Piero Barboni ¹³ , Michele Carbonelli ⁹ , Maria Lucia Valentino ¹ ⁹ , Rocco Liguori ¹ ⁹ , Vandana Shashi ¹⁴ , Jennifer Sullivan ¹⁴ , Shashi Nagaraj ¹⁵ , Mays El-Dairi ¹⁶ , Alessandro Iannaccone ¹⁷ , Ioana Cutcutache ¹⁸ , Enrico Bertini ¹⁹ , Rosalba Carrozzo ¹⁹ , Francesco Emma ²⁰ , Francesca Diomedi-Camassei ²¹ , Claudia Zanna ²² , Martin Armstrong ²³ , Matthew Page ¹⁸ , Nicholas Stong ¹⁰ , Sylvia Boesch ²⁴ , Robert Kopajtich ⁷ ⁸ , Saskia Wortmann ⁷ ⁸ ²⁵ , Wolfgang Sperl ²⁵ , Erica E Davis ² , William C Copeland ¹² , Marco Seri ⁶ ²⁶ , Maria Falkenberg ¹¹ , Holger Prokisch ⁷ ⁸ , Nicholas Katsanis ² ²⁷ ²⁸ , Valeria Tiranti ⁵ , Tommaso Pippucci ⁶ , Valerio Carelli ¹ ⁹

Affiliations

1. Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
2. Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.
3. Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
4. Pakistan Institute of Engineering and Applied Sciences (PIEAS), Faisalabad, Pakistan.
5. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
6. Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Bologna, Italy.
7. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
8. Institute of Human Genetics, Technische Universität München, Munich, Germany.
9. IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy.
10. Institute for Genomic Medicine, Columbia University, New York, New York, USA.
11. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
12. Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
13. Department of Ophthalmology, Studio Oculistico d'Azeglio, Bologna, Italy.
14. Division of Medical Genetics and.
15. Division of Nephrology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
16. Neuro-Ophthalmology Service and.
17. Center for Retinal Degenerations and Ophthalmic Genetic Diseases and Visual Function Diagnostic Laboratory, Duke Eye Center, Duke University School of Medicine, Durham, North Carolina, USA.
18. Translational Medicine, UCB Pharma, Slough, United Kingdom.
19. Unit of Muscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
20. Division of Nephrology, Department of Pediatric Subspecialties, Bambino Gesù Children's Hospital, Rome, Italy.
21. Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, Rome, Italy.
22. Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy.
23. Translational Medicine, UCB Pharma, Braine-l'Alleud, Belgium.
24. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
25. Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University Salzburg, Salzburg, Austria.
26. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
27. Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
28. Departments of Pediatrics and Cellular and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

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.

Keywords

Bioenergetics; Genetic diseases; Genetics; Mitochondria; Ophthalmology.