Low “penetrance” of phylogenetic knowledge in mitochondrial disease studies

An up-to-date view of the worldwide mitochondrial DNA (mtDNA) phylogeny together with an evaluation of the conservation of each site is a reliable tool for detecting errors in mtDNA studies and assessing the functional importance of alleged pathogenic mutations. However, most of the published studies on mitochondrial diseases make very little use of the phylogenetic knowledge that is currently available. This drawback has two inadvertent consequences: first, there is no sufficient a posteriori quality assessment of complete mtDNA sequencing efforts; and second, no feedback is provided for the general mtDNA database when apparently new mtDNA lineages are discovered. We demonstrate, by way of example, these issues by reanalysing three mtDNA sequencing attempts, two from Europe and another one from East Asia. To further validate our phylogenetic deductions, we completely sequenced two mtDNAs from healthy subjects that nearly match the mtDNAs of two patients, whose sequences gave problematic results. (c) 2005 Elsevier Inc. All rights reserved.

Strikingly different penetrance of LHON in two Chinese families with primary mutation G11778A is independent of mtDNA haplogroup background and secondary mutation G13708A

The penetrance of Leber's hereditary optic neuropathy (LHON) in families with primary mitochondrial DNA (mtDNA) mutations is very complex. Matrilineal and nuclear genetic background, as well as environmental factors, have been reported to be involved in d

High penetrance of sequencing errors and interpretative shortcomings in mtDNA sequence analysis of LHON patients

For identifying mutation(s) that are potentially pathogenic it is essential to determine the entire mitochondrial DNA (mtDNA) sequences from patients suffering from a particular mitochondrial disease, such as Leber hereditary optic neuropathy (LHON). Howe

Co-occurrence of A1555G and G11778A in a Chinese family with high penetrance of Leber's hereditary optic neuropathy

Co-occurrence of double pathogenic mtDNA mutations with different claimed pathological roles in one mtDNA is infrequent. It is tentative to believe that each of these pathogenic mutations would have its own deleterious effect. Here we reported one three-g

Mitochondrial DNA Haplogroups M7b1 ' 2 and M8a Affect Clinical Expression of Leber Hereditary Optic Neuropathy in Chinese Families with the m.11778G -> A Mutation

Leber hereditary optic neuropathy (LHON) is the most extensively studied mitochondrial disease, with the majority of the cases being caused by one of three primary mitochondrial DNA (mtDNA) mutations. Incomplete disease penetrance and gender bias are two

Molecular characterization of six Chinese families with m.3460G > A and Leber hereditary optic neuropathy

The primary mutation m.3460G > A occurs with a very low frequency (similar to 1%) in Chinese patients with Leber hereditary optic neuropathy (LHON). Up to now, there is no comprehensive study of Chinese patients harboring this mutation. We characterized six unrelated probands with m.3460G > A in this study, which were identified from 1,626 patients with LHON or suspected with LHON. The overall penetrance of LHON (25.6% [10/39]) in four pedigrees with m.3460G > A was substantially lower than those families with m.11778G > A (33.3% [619/1859]) as reported in our previous study. Intriguingly, family Le688 with a heteroplasmic m.3460G > A presented a lower penetrance (12.5%) than the other three families with a homoplasmic mutation. There is an elevated gender bias (affected male to affected female = 4:1) in the four families with m.3460G > A compared to those LHON families with m.11778G > A (2.4:1). Complete mtDNA sequencing indicated that the six matrilines belonged to haplogroups B4d1, F2, A5b, M12a, D4b2b, and D4b2, respectively. We did not identify any potential secondary mutation(s) that will affect or be associated with the penetrance of LHON in the six probands by using an evolutionary analysis and protein secondary-structure prediction. Taken together, our results suggested that the m.3460G > A mutation occurred multiple times in Chinese LHON patients. The heteroplasmic status of mutation m.3460G > A might influence the penetrance of LHON in family Le688.

mtDNA haplogroup distribution in Chinese patients with Leber's hereditary optic neuropathy and G11778A mutation

Mitochondrial DNA background has been shown to be involved in the penetrance of Leber's hereditary optic neuropathy (LHON) in western Eurasian populations. To analyze mtDNA haplogroup distribution pattern in Han Chinese patients with LHON and G11778A muta