SSBP1 – Leigh syndrome

A de novo heterozygous missense variant in SSBP1 has been reported in a patient presenting a mitochondrial DNA maintenance defect with clinical features spanning Pearson, Kearns-Sayre, and Leigh syndromes. On trio whole-exome sequencing, a 14-year-old boy was found to harbor c.79G>A (p.Glu27Lys) in SSBP1, associated with infantile anemia, pancytopenia, growth delay, ptosis, ophthalmoplegia, ataxia, sensorineural hearing loss, chronic kidney disease, and metabolic strokes ([PMID:31479473]). This single proband represents the primary genetic evidence linking SSBP1 to Leigh syndrome, with no additional affected relatives identified.

Biochemical and biophysical analyses demonstrated that p.Glu27Lys SSBP1 forms stable tetramers but exhibits modestly decreased thermostability and altered single-stranded DNA binding relative to wild type, consistent with a dominant-negative mechanism impairing mtDNA replication ([PMID:31479473]). Molecular modeling confirmed surface-accessible charge alterations that likely disrupt replisome interactions. These functional data provide moderate experimental support for pathogenicity in humans and recapitulate key aspects of mtDNA maintenance defects observed in Leigh syndrome.

Key take-home: SSBP1 should be considered in the genetic workup of Leigh syndrome, though additional cases are needed to strengthen clinical validity.

References

• PloS one • 2019 • Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes. PMID:31479473
• The Journal of biological chemistry • 2011 • Reduced stimulation of recombinant DNA polymerase γ and mitochondrial DNA (mtDNA) helicase by variants of mitochondrial single-stranded DNA-binding protein (mtSSB) correlates with defects in mtDNA replication in animal cells. PMID:21953457

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