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SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder.

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.

SUBMITTER: Del Dotto V

PROVIDER: S-EPMC6934201 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder.

Del Dotto Valentina V Ullah Farid F Di Meo Ivano I Magini Pamela P Gusic Mirjana M Maresca Alessandra A Caporali Leonardo L Palombo Flavia F Tagliavini Francesca F Baugh Evan Harris EH Macao Bertil B Szilagyi Zsolt Z Peron Camille C Gustafson Margaret A MA Khan Kamal K La Morgia Chiara C Barboni Piero P Carbonelli Michele M Valentino Maria Lucia ML Liguori Rocco R Shashi Vandana V Sullivan Jennifer J Nagaraj Shashi S El-Dairi Mays M Iannaccone Alessandro A Cutcutache Ioana I Bertini Enrico E Carrozzo Rosalba R Emma Francesco F Diomedi-Camassei Francesca F Zanna Claudia C Armstrong Martin M Page Matthew M Stong Nicholas N Boesch Sylvia S Kopajtich Robert R Wortmann Saskia S Sperl Wolfgang W Davis Erica E EE Copeland William C WC Seri Marco M Falkenberg Maria M Prokisch Holger H Katsanis Nicholas N Tiranti Valeria V Pippucci Tommaso T Carelli Valerio V

The Journal of clinical investigation 20200101 1

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 in ...[more]

PMID: 31550240

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Project description:MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

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SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder.

Publications

SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder.

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