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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy
Journal of Clinical Investigation, Volume 130, No. 1, Year 2020
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Description
Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders. © 2020, Piro-Mégy et al.
Authors & Co-Authors
Piro-Mégy, Camille
France, Montpellier
Université de Montpellier
Péquignot, Marie O.
France, Montpellier
Université de Montpellier
Quilès, Mélanie
France, Montpellier
Université de Montpellier
Manès, Gaël
France, Montpellier
Université de Montpellier
Sénéćhal, Audrey
France, Montpellier
Université de Montpellier
Bocquet, Béatrice
France, Montpellier
Université de Montpellier
France, Montpellier
Centre Hospitalier Universitaire de Montpellier
Roubertie, Agathe
France, Montpellier
Université de Montpellier
France, Montpellier
Centre Hospitalier Universitaire de Montpellier
Charif, Majida
France, Paris
Inserm
Goudenège, David
France, Paris
Inserm
Lenaers, Guy
France, Paris
Inserm
Wilhelm, Helmut M.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Kellner, Ulrich
Unknown Affiliation
Weisschuh, Nicole
Germany, Tubingen
Eberhard Karls Universität Tübingen
Wissinger, Bernd
Germany, Tubingen
Eberhard Karls Universität Tübingen
Zanlonghi, Xavier
France, Nantes
Centre de Compétence Maladie Rares
Hamel, Christian P.
France, Montpellier
Université de Montpellier
France, Montpellier
Centre Hospitalier Universitaire de Montpellier
Spelbrink, Johannes N.
Netherlands, Nijmegen
Radboud University Medical Center
Delettre, Cécile
France, Montpellier
Université de Montpellier
Statistics
Citations: 39
Authors: 18
Affiliations: 7
Identifiers
Doi:
10.1172/JCI128513
ISSN:
00219738
Research Areas
Genetics And Genomics
Health System And Policy