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Valerio Carelli, Leonardo Caporali, Francesca Tagliavini, Chiara La Morgia, Alessandro Achilli, Anna Olivieri, Antonio Torroni; The landscape of mitogenomes from LHON patients carrying the m.14484T>C/MT-ND6 mutation. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3601.
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© ARVO (1962-2015); The Authors (2016-present)
Leber’s Hereditary Optic Neuropathy (LHON) is associated in 90% of cases with one of three mitochondrial DNA (mtDNA) point mutations affecting complex I: m.11778G>A/MT-ND4, m.14484T>C/MT-ND6 and m.3460G>A/MT-ND1. The m.14484T>C/MT-ND6 mutation is peculiar for being tightly associated with haplogroup J, which is believed to increase its penetrance. Furthermore, this mutation is also the mildest due to the high rate of visual recovery, and is weakly penetrant in females (male:female=8:1). Last, this mutation has also been found in control populations, behaving as borderline polymorphic variant. We revisited the genetic landscape of this mutation assembling the largest cohort ever of families (155 probands) from Europe and the US, investigated by complete mtDNA sequence analysis.
Sequencing of the entire mitogenome was performed on a MiSeq platform (Illumina) in 155 LHON probands of European ancestry harboring the m.14484T>C/MT-ND6 mutation, after long-range amplification of each mitogenome in two PCR fragments and library preparation using Nextera XT technology.
Out of the entire cohort 36 probands were found to be related by 11 mutational events (identical sequences), and phylogenetic analyses highlighted the occurrence of frequent founder events clustering shared haplotypes with one or two variants distance. Haplotype classification confirmed the previously reported association with haplogroup J (54%), but without a preferential clustering on specific sub-clades. Each private missense variant was evaluated to assess its potential synergic role and recurrence of secondary mutations emerged in 13 cases. Except for the m.3460G>A/MT-ND1 and m.11778G>A/MT-ND6, which are primary pathogenic mutations (“double troubles”), the remaining coexisting missense variants, i.e m.4136A>G/MT-ND1, m.4160T>C/MT-ND1, m.4184T>A/MT-ND1, m.4659G>A/MT-ND2, m.10237T>C/MT-ND3, were all considered as possibly pathogenic or with a synergistic role, some of them being recurrent on haplogroup J.
In conclusion, the association of the m.14484T>C/MT-ND6 mutation with the J branch of the mtDNA tree highlights a complex interplay, reveals multiple founder events in Europe after geographic mitogenome stratification and raises the possibility that certain mitogenomes may be predisposed to mutagenesis.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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