Candidate Modifier Genes for the Penetrance of Leber’s Hereditary Optic Neuropathy

Abstract

Leber’s hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute visual loss predominantly affecting young men. The mtDNA mutation is transmitted to all maternal lineages. However, only approximately 50% of men and 10% of women harboring a pathogenic mtDNA mutation develop optic neuropathy, reflecting both the incomplete penetrance and its unexplained male prevalence, where over 80% of patients are male. Nuclear modifier genes have been presumed to affect the penetrance of LHON. With conventional genetic methods, prior studies have failed to solve the underlying pathogenesis. Whole exome sequencing (WES) is a new molecular technique for sequencing the protein-coding region of all genes in a whole genome. We performed WES from five families with 17 members. These samples were divided into the proband group (probands with acute onset of LHON, n = 7) and control group (carriers including mother and relative carriers with mtDNSA 11778 mutation, without clinical manifestation of LHON, n = 10). Through whole exome analysis, we found that many mitochondria related (MT-related) nuclear genes have high percentage of variants in either the proband group or control group. The MT genes with a difference over 0.3 of mutation percentage between the proband and control groups include AK4, NSUN4, RDH13, COQ3, and FAHD1. In addition, the pathway analysis revealed that these genes were associated with cofactor metabolism pathways. Family-based analysis showed that several candidate MT genes including METAP1D (c.41G > T), ACACB (c.1029del), ME3 (c.972G > C), NIPSNAP3B (c.280G > C, c.476C > G), and NSUN4 (c.4A > G) were involved in the penetrance of LHON. A GWAS (genome wide association study) was performed, which found that ADGRG5 (Chr16:575620A:G), POLE4 (Chr2:7495872T:G), ERMAP (Chr1:4283044A:G), PIGR (Chr1:2069357C:T;2069358G:A), CDC42BPB (Chr14:102949A:G), PROK1 (Chr1:1104562A:G), BCAN (Chr 1:1566582C:T), and NES (Chr1:1566698A:G,1566705T:C, 1566707T:C) may be involved. The incomplete penetrance and male prevalence are still the major unexplained issues in LHON. Through whole exome analysis, we found several MT genes with a high percentage of variants were involved in a family-based analysis. Pathway analysis suggested a difference in the mutation burden of MT genes underlining the biosynthesis and metabolism pathways. In addition, the GWAS analysis also revealed several candidate nuclear modifier genes. The new technology of WES contributes to provide a highly efficient candidate gene screening function in molecular genetics.

Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair

“…Nuclear modifier genes have been presumed to affect the penetrance of LHON, but conventional genetic methods have failed to clarify these issues. Cheng et al [ 16 ] performed both whole exome sequencing (WES), a technique used to capture all genetic variations, and genome-wide association studies (GWAS), that generally involve targeted genotyping of specific and pre-selected variants using microarrays, to assess seventeen members of five families, all of whom had the 11778 mutation. Seven of these members had LHON, whereas ten were asymptomatic carriers.…”

Impact of Protein Nα-Modifications on Cellular Functions and Human Health

“…Improper neuronal function from losing essential proteins could lead to neurologic impairment and ID [91]. In addition, a mutation in the MetAP1D gene was identified as one candidate involved in the penetrance of Leber's hereditary optic neuropathy (LHON) [92]. Though we are still very early in understanding how mutations in MetAPs could affect human health, NME excision processes provide a promising avenue in translational research.…”

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial

“… 3 However, the penetrance of LHON is incomplete and variable and can therefore not be explained by a single point mutation of mtDNA alone. 5 , 6 , 7 , 8 , 9 , 10 Worldwide, approximately 90% of patients carry one of three common mtDNA mutations, m.11778G>A in MT-ND4 , m.3460G>A in MT-ND1 , and m.14484T>C in MT-ND6 . 2 This proportion can vary by region.…”