Leber's Hereditary Optic Neuropathy: A Report on Novel mtDNA Pathogenic Variants

Abstract

Leber's hereditary optic neuropathy (LHON) is due to missense point mutations affecting mitochondrial DNA (mtDNA); 90% of cases harbor the m.3460G>A, m.11778G>A, and m.14484T>C primary mutations. Here, we report and discuss five families with patients affected by symptomatic LHON, in which we found five novel mtDNA variants. Remarkably, these mtDNA variants are located in complex I genes, though without strong deleterious effect on respiration in cellular models: this finding is likely linked to the tissue specificity of LHON. This study observes that in the case of a strong clinical suspicion of LHON, it is recommended to analyze the whole mtDNA sequence, since new rare mtDNA pathogenic variants causing LHON are increasingly identified.

Keywords: LHON; Leber optic atrophy; complex I; mitochondrial respiratory chain; transmitochondrial cybrids.

Figure 1

Mitochondrial respiratory chain activities on fibroblasts and cybrids. (A) Mitochondrial respiratory chain activities of CI and CIV complexes in Patient 3 (PT3), Patient 4 (PT4), Patient 6 (PT6) fibroblasts, and mediated controls (six different fibroblast cell lines) cultured in glucose-rich DMEM medium. (B) Mitochondrial respiratory chain activities of CI and CIV complexes in Patient 6 cybrids cultured in glucose-rich DMEM (PT6) and 5 mediated trans-mitochondrial cybrids controls (CT) grown in the same medium. Enzymatic activities (nmol/min/mg of protein) are expressed in percentage compared to controls and normalized with citrate syntase (CS) activity (blue column). CI, complex I (red column); CIV, complex IV (orange column). Student's t-test *p ≤ 0.05.