Co-segregation and heteroplasmy of two coding-region mtDNA mutations within a matrilineal pedigree

Abstract

The ENG1 Leber's hereditary optic neuropathy (LHON) family spans six generations and comprises more than 90 maternally related individuals. In this pedigree, the G:A LHON mutation at nucleotide position 11778 shows a complex pattern of segregation in which it is homoplasmic mutant in two branches, homoplasmic wildtype in another, and heteroplasmic in a fourth branch. In addition, there is co-segregation of the 11778 mutant allele and of a G:A silent polymorphism at nucleotide position 5471 in 18 of 19 family members. This co-segregation indicates that the two substitutions arose either simultaneously, or nearly so, in the same "founder" mtDNA molecule. However, the highly divergent mitochondrial allele ratios in the one family member suggest that there has been a complex origin and segregation "history" of these two substitutions. Taking all of the results into consideration, the evidence supports sequential single mutations at sites 5471 and 11778, in close temporal proximity, with subsequent segregation of the intermediate mutational genotype to high levels in one branch of the ENG1 LHON family. In other branches, either the double wildtype or double mutant genotype has become essentially homoplasmic.

The Mutant Human ND4 Subunit of Complex I Induces Optic Neuropathy in the Mouse

“…Resolution of optic disc swelling was followed by optic atrophy in our mice. Unlike human LHON that requires 100% mutated G11778A mtDNA for expression of the phenotype, 3,17,18 ocular injury in our model system was initiated by expression of the mutant human complex I subunit in murine mitochondria with a normal genome. Thus, in the mouse it appeared to have a dominant impact.…”

Inheritance of Mitochondrial DNA Recombinants in Double-Heteroplasmic Families: Potential Implications for Phylogenetic Analysis

“…Recent reports provided evidence that long-persisting heteroplasmy appears to not be an exclusive feature of certain pathogenic mutations; rather, it is also a feature of D-loop polymorphisms. 16,17 Whether two heteroplasmic instances of a specific mtDNA mutation occurred independently or are related (i.e., originate from a single mutation event and have been inherited in the heteroplasmic state) may be difficult to distinguish. Since members of the published families 16,17 carry heteroplasmy at the same site, inheritance of heteroplasmy in these families is more plausible, unless one assumes a family-specific and site-specific instability of the mitochondrial genome.…”

“…16,17 Whether two heteroplasmic instances of a specific mtDNA mutation occurred independently or are related (i.e., originate from a single mutation event and have been inherited in the heteroplasmic state) may be difficult to distinguish. Since members of the published families 16,17 carry heteroplasmy at the same site, inheritance of heteroplasmy in these families is more plausible, unless one assumes a family-specific and site-specific instability of the mitochondrial genome. In respect to the both D-loop sites-A16182C and G16428A-investigated in our report, we conclude from comparison with database sequences and a screening of a large collection of brain and muscle sample that heteroplasmy at these sites is rare.…”

Transmission of heteroplasmic G11778A in extensive pedigrees of Thai Leber hereditary optic neuropathy

“…In each of these two families, the G11778A mutation load was 18% in the blood of the maternal ancestor, but it was not detectable at all in the blood of her siblings, indicating that the mutation may be a relatively new occurrence in the germ-line of their mother. However, another possibility would be that the mutation had existed before but did not segregate to her siblings (Howell et al 2005). MtDNA samples from other informative maternal relatives would be required to confirm the two de novo occurrences of the mutation.…”