SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder

Area of Science:

• Genetics
• Mitochondrial Biology
• Ophthalmology

Background:

• Inherited optic neuropathies often involve mitochondrial dysfunction.
• Mitochondrial DNA (mtDNA) depletion is a key factor in these disorders.
• Previous research has not fully elucidated the genetic causes of mtDNA depletion syndromes.

Purpose of the Study:

• To identify the genetic basis of an optic atrophy spectrum disorder with kidney involvement.
• To investigate the functional consequences of identified mutations on mtDNA maintenance.
• To establish SSBP1 as a causative gene for this inherited condition.

Main Methods:

• Whole-exome sequencing was used to identify mutations in affected families.
• Patient-derived fibroblasts were analyzed for SSBP1 protein levels, multimer formation, and ssDNA binding.
• mtDNA, nucleoids, and 7S-DNA amounts were quantified.
• Mitochondrial function assays (respiratory efficiency, OXPHOS) were performed.
• Zebrafish models were utilized to assess in vivo phenotypes.

Main Results:

• Mutations in SSBP1 were identified in families with dominant and recessive inheritance patterns.
• SSBP1 mutations led to variable protein levels and altered multimer formation, impairing mtDNA replication.
• Significant mtDNA depletion and mitochondrial dysfunction were observed in patient cells and tissues.
• Zebrafish models with suppressed ssbp1 exhibited kidney and optic nerve abnormalities.

Conclusions:

• SSBP1 mutations are a novel cause of inherited optic neuropathy and a spectrum of related disorders.
• The findings highlight the critical role of SSBP1 in mtDNA maintenance and replication.
• This study establishes a new genetic basis for mitochondrial DNA depletion syndromes.