In surveying our current knowledge of the biochemical components of the mtDNA replication machinery, it is striking that mutations in POLG/POLG2 and TWNK lead to progressive ophthalmoplegia, while mutations in SSBP1 have recently been found to cause optic atrophy and retinal degeneration. All four gene products form together on the replication machinery therefore one might expect highly overlapping phenotypes. SSBP1 is essential for mtDNA replication and maintenance, its downregulation or dysfunction may be expected to affect mtDNA copy number, resulting in mitochondrial morphological and functional changes, including accumulation of reactive oxygen species in mitochondria.
We have recently reported detailed genetic, clinical and electrophysiological features in similarly affected individuals from four families with early onset bilateral optic neuropathy and subsequent retinal degeneration. We have identified missense variants affecting highly conserved amino acid residues in the ssDNA binding domain of SSBP1 and their association with disease. Antisense-mediated knockdown of endogenous ssbp1 mRNA in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point to an essential role of ssbp1 in retinal development.
This finding broadens the genes that should be screened in patients displaying optic atrophy and retinal degeneration and has implications for genetic testing and counseling.