Mutation analysis of Leber's hereditary optic neuropathy using a multi‑gene panel

Abstract

Abstract. The present study investigates the spectrum and incidence of mitochondrial DNA (mtDNA) mutations associated with Leber's hereditary optic neuropathy (LHON) in a Han population using a multi-gene panel with 46 LHON-associated mutations among 13 mitochondrial genes. A total of 23 mutations were observed in a cohort of 275 patients and 281 control subjects using multi-gene panel analysis IntroductionLeber's hereditary optic neuropathy (LHON; OMIM 535000) is a classic mitochondrial disease, associated with a rapid, painless, acute or sub-acute bilateral visual loss in young adults, predominantly caused by the primary and secondary mutations in mitochondrial DNA (mtDNA). It has been reported that 1:8,500 individuals harbor a primary LHON-causing mutation and 1:31,000 experience visual loss as a result of LHON in the North East of England (1). Few significant improvements in visual acuity are reported following atrophy of the optic discs. LHON typically affects males more frequently than females, with the incomplete and variable penetrance estimated at ~50% in males and 10% in females (2-4). Additionally, certain LHON cases have additional clinical symptoms, such as movement disorders, dystonia, and multiple-sclerosis-like illness, which complicate the diagnosis in the clinical setting (5-7). Although the majority ofcases of LHON transmitted by maternal inheritance have a history of visual loss in families, up to 40% of cases are sporadic (5).The genetic cause of LHON is mutations in the mitochondrial genome, which is a double-stranded 16,569-nucleotide pair, circular molecule, consisting of one D-Loop region and 37 genes. The three most causative mutations, m.11778G>A (M T-ND4), m.14484T>C (M T-ND6) and m.3460G>A (MT-ND1), have been reported to account for 90% of LHON patients in a Caucasian population, but for only 38.3 and 46.5% of cases in two large cohorts of Chinese Han subjects with LHON (7-10). Our previous studies have shown the spectrum of genes, MT-ND1, MT-ND4 and MT-ND6, and the frequency of the three primary mutations in a Chinese LHON population (8-10) using Sanger sequencing. In addition, secondary mutations that contributed to the high penetrance,

Mitochondrial genome variation in male LHON patients with the m.11778G > A mutation

“…Screening for the presence of other proven pathogenic variants in mtDNA, both point mutations and large deletions, brought negative results, implying that such deleterious changes do not contribute to disease development. Nevertheless, we identified three non-synonymous variants reported previously to associate with LHON (Fauser et al 2002;Abu-Amero and Bosley 2006;Dai et al 2018). However, their role in disease development in a synergistic mechanism, as an additional, secondary mutation, in three Table 4 Number of transitions (T S ), transversions (T V ), and their ratio in particular mtDNA regions in male LHON patients and control subjects.…”

“…No other proven pathogenic variants were found either in LHON patients or control individuals. However, three distinct mtDNA variants reported previously to associate with LHON (Fauser et al 2002;Abu-Amero and Bosley 2006;Dai et al 2018) were identified in three different patients and one control subject, in all in the homoplasmic state, and are shown in more detail in Table 1. All three variants define haplogroups on the background of which they were detected in patients (Oven and Kayser 2009).…”

Enrichment of retinal ganglion and Müller glia progenitors from retinal organoids derived from human induced pluripotent stem cells - possibilities and current limitations

“…The damage and eventual loss of RGCs in DOA are caused by the progressive impairment of mitochondrial oxidation and the lack of energy production in the form of ATP through the mitochondrial respiratory chain. Causative mutations for LHON affect members of the gene family encoding the mitochondrially encoded NADH: Ubiquinone oxidoreductase core subunits ( MT-ND1, MT-ND4, MT-ND5 and MT-ND6 )[ 7 ]. These mutations affect complex 1 of the electron transport chain of the mitochondria and manifest in failure of oxidative pho-sphorylation accompanied by impaired or absent ATP production.…”

Leber's Hereditary Optic Neuropathy–Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family

“…Leber's hereditary optic neuropathy (LHON) is one of the most common mitochondrial DNA (mtDNA) diseases, which is characterized by acute or subacute bilateral central vision loss due to selective death of retinal ganglion cells (RGCs) and optic atrophy 1–3. The disease is typically detected in young adults and more frequently affects males, predominantly 4.…”