Mitochondrial genome variation in male LHON patients with the m.11778G\u2009>\u2009A mutation

Agnieszka Piotrowska-Nowak,Maciej R Krawczyński,Anna M Ambroziak,Magdalena Korwin,Ewa Kosior-Jarecka,Katarzyna Tońska,Monika Ołdak,Ewa Bartnik

doi:10.1007/s11011-020-00605-3

Abstract

Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with symptoms limited to a single tissue, optic nerve, resulting in vision loss. In the majority of cases it is caused by one of three point mutations in mitochondrial DNA (mtDNA) but their presence is not sufficient for disease development, since ~50% of men and ~10% women who carry them are affected. Thus additional modifying factors must exist. In this study, we use next generation sequencing to investigate the role of whole mtDNA variation in male Polish patients with LHON and m.11778G > A, the most frequent LHON mutation. We present a possible association between mtDNA haplogroup K and variants in its background, a combination of m.3480A > G, m.9055G > A, m.11299 T > C and m.14167C > T, and LHON mutation. These variants may have a negative effect on m.11778G > A increasing its penetrance and the risk of LHON in the Polish population. Surprisingly, we did not observe associations previously reported for m.11778G > A and LHON in European populations, particularly for haplogroup J as a risk factor, implying that mtDNA variation is much more complex. Our results indicate possible contribution of novel combination of mtDNA genetic factors to the LHON phenotype.

Highlights

Transmitted pathogenic variants of mitochondrial DNA may lead to dysfunction of the oxidative phosphorylation system and the development of mitochondrial diseases, a heterogeneous group of usually multi-organ disorders that can occur at any age
Bioinformatic analysis workflow consisted of quality control of sequencing reads, mapping to the human mitochondrial DNA (mtDNA) reference sequence, variant detection, annotation and evaluation based on the strategy described in detail previously (Piotrowska-Nowak et al 2018). mtDNA haplogroup assignment was performed for each subject using all variants identified in their mtDNA and the Mitomaster tool (Lott et al 2013)
In this study we investigated the mtDNA sequence variation in male Leber hereditary optic neuropathy (LHON) patients with the m.11778G > A mutation and control male subjects

Summary

Introduction

Transmitted pathogenic variants of mitochondrial DNA (mtDNA) may lead to dysfunction of the oxidative phosphorylation system and the development of mitochondrial diseases, a heterogeneous group of usually multi-organ disorders that can occur at any age. The m.11778G > A point mutation was one of the first mtDNA pathogenic variants to be associated with human disease (Wallace et al 1988). It was described in patients with hereditary predisposition to blindness, a disease known as Leber hereditary optic neuropathy (LHON) (Wallace et al 1988). Extended author information available on the last page of the article

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