Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDS), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in SSBP1 in five 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 new revised SSBP1 crystal structure. Structural analysis suggests 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 novel form of dominant optic atrophy frequently accompanied with foveopathy, brings new insights into mtDNA maintenance disorders.
-
Want to know more about these subjects? Click on the buttons below for more news.
Related news items
BCG vaccine is safe with no increased risk of COVID-19 symptoms says Mihai Netea
11 August 2020The BCG vaccine has a general stimulating effect on the immune system and is therefore effective against multiple infectious diseases - possibly also against COVID-19.
read more
650,000 Euro funding for research into the phasing out of medication for leukaemia patients
30 July 2020With a 650,000 euro funding from ZonMw, researchers from the Haematology and Pharmacy departments can develop a medication phasing out strategy for patients with chronic myeloid leukaemia. This strategy will be tested in practice.
read more
Increased role of patients after bowel cancer treatment
30 July 2020Approximately 14,000 patients get colorectal cancer every year. Almost all patients are operated on and monitored afterwards (follow-up). In 2019 Radboudumc started a new approach to follow-up research after the treatment of stage II/III colorectal cancer.
read more
ERC Proof of Concept grant received by Ronald van Rij
30 July 2020Ronald van Rij, theme Infectious diseases and global health, received an ERC (European Research Council) Proof of Concept grant of 150,000 euros, in order to make arbovirus vaccines even safer.
read more
Hypatia fellowship Call is open
30 July 2020The Hypatia fellowship round with the deadline 31 May has been canceled. Therefore, the next available deadline will be 27 September 2020. Radboudumc researchers are invited to scout young potentials to fill the strategic gaps within the research themes imbedded in RIHS and RIMLS.
read more
Mihai Netea and colleagues published two papers back-to-back in The Journal of Clinical Investigation.
29 July 2020These back-to-back articles investigated the effect of BCG vaccination on trained immunity. The first article shows that BCG vaccination inhibits systemic inflammation, depending on gender. The second article demonstrates that the circadian rhythm influences the induction of trained immunity.
read more