Several factors have been proposed as contributors to interfamilial and intrafamilial phenotypic variability in autosomal dominant disorders, including allelic variation, modifier genes, environmental factors and complex genetic and environmental interactions. However, regardless of the similarity of genetic background and environmental factors, asymmetric limb or trunk anomalies in a single individual and variable manifestation between monozygotic twins have been observed, indicating other mechanisms possibly involved in expressivity of autosomal dominant diseases. One such example is Holt-Oram syndrome (HOS), which is characterized by congenital cardiac defects and forelimb anomalies, mainly attributed to mutations in the TBX5 gene. We hypothesize that monoallelic expression of the TBX5 gene occurs during embryo development, and, in the context of a mutation, random monoallelic expression (RME) can create discrepant functions in a proportion of cells and thus contribute to variable phenotypes. A hybrid mouse model was used to investigate the occurrence of RME with the Tbx5 gene, and single-cell reverse transcription PCR and restriction digestion were performed for limb bud cells from developing embryos (E11.5) of the hybrid mice. RME of Tbx5 was observed in approximately two-thirds of limb bud cells. These results indicate that RME of the Tbx5 gene occurs frequently during embryo development, resulting in a mosaic expression signature (monoallelic, biallelic, or null) that may provide a potential explanation for the widespread phenotypic variability in HOS. This model will further provide novel insights into the variability of autosomal dominant traits and a better understanding of the complex expressivity of disease conditions.

Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.