Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy

Hereditary optic neuropathies (HON) are blinding conditions that affect the optic nerve which connects the eye to the brain. Mitochondrial (mt) and nuclear DNA mutations can cause HON. mtDNA mutations in complex I subunits of the respiratory chain cause a bilateral, painless, subacute disease known as Leber HON (LHON). Here, we report for the first time a LHON-like phenotype associated with a nuclear gene, NDUFS2. Consistent with the pathomechanism of LHON, NDUFS2 is required for the assembly of Complex I. Severe NDUFS2 mutations were previously reported to cause Leigh syndrome. Our results suggest milder mutations can cause isolated HON. (By Dr. Jean-Michel ROZET, )