Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy

Abstract

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.

De Novo Development of mtDNA Deletion Due to Decreased POLG and SSBP1 Expression in Humans

“…The second-highest-rank variant, c.320G>A (p. [Arg107Gln]), in the SSBP1 gene has been reported as an autosomal dominant mutation associated with optic atrophy disorder and severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns–Sayre, and Leigh syndrome spectrum [ 17 , 25 , 26 , 27 ].…”

TWINKLE and Other Human Mitochondrial DNA Helicases: Structure, Function and Disease

“…In addition, DNA replication assays combining mutant TWINKLE variants with mtSSB and POLγ suggest that disease-causing mutations have a strong negative effect on these protein-protein interactions (see Section 2.2) [28,39]. Newly reported disease-causing mutations in mtSSB could also help shed light on these interactions and provide evidence for specific functional and physical interactions between TWINKLE and mtSSB [88,89].…”

Mammalian mitochondrial DNA replication and mechanisms of deletion formation

“…Interestingly, disease-causing mutations have recently been identified in the gene coding for mtSSB. The mutant proteins bind ssDNA less efficiently and mtDNA is depleted in affected individuals (Gustafson et al 2019;Piro-Megy et al 2019;Del Dotto et al 2020) An indepth analysis of replication intermediates in patientderived cell lines may provide important insights about possible priming outside the OriL region.…”