Whole Mitochondrial Genome Analysis in Serbian Cases of Leber's Hereditary Optic Neuropathy

Abstract

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder that affects central vision in young adults and is typically associated with mitochondrial DNA (mtDNA) mutations. This study is based on a mutational screening of entire mtDNA in eight Serbian probands clinically and genetically diagnosed with LHON and four of their family members, who are asymptomatic mutation carriers. All obtained sequence variants were compared to human mtDNA databases, and their potential pathogenic characteristics were assessed by bioinformatics tools. Mitochondrial haplogroup analysis was performed by MITOMASTER. Our study revealed two well-known primary LHON mutations, m.11778G>A and m.3460G>A, and one rare LHON mutation, m.8836A>G. Various secondary mutations were detected in association with the primary mutations. MITOMASTER analysis showed that the two well-known primary mutations belong to the R haplogroup, while the rare LHON m.8836A>G was detected within the N1b haplogroup. Our results support the need for further studies of genetic background and its role in the penetrance and severity of LHON.

Keywords: Leber’s hereditary optic neuropathy; haplogroups; mtDNA; mutations.

Figure 1

Pedigrees of two analyzed Leber’s hereditary optic neuropathy (LHON) families. I:1 not assessed, a halved circle/square = asymptomatic mutation carrier, Het = heteroplasmy.

Figure 2

Schematic phylogenetic tree encompassing the complete mtDNA genome from eight Serbian probands with pathogenic LHON mutations. The tree was rooted by following the nomenclature of mtDNA tree Build 17, using the reference sequence rCRS haplogroup (H2a2a). Underlining indicates recurrent mutations; suffixes indicate back mutations (!), non-coding region (nc), synonymous variants (s), nonsynonymous variants (ns). Variations in the transfer RNA and the ribosomal RNA1, and 2 genes are denoted by (t), (r₁), and (r₂), respectively. Previous mtDNA sequences that have showed the association of m.3394 variant on haplogroup M9a background in Chinese families, are added (GenBank accession number FJ748744 and FJ748758, [49]). The arrows indicate the nonsynonymous mutations that might have a potential role in LHON expression. LHON primary mutations are shown in bold and were added to the tree after phylogeny tree construction.