Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer

Transfer of nucleic acid from cytoplasmic organelles to the nuclear genome is a well-established mechanism of evolutionary change in eukaryotes. Such transfers have occurred throughout evolution, but so far, none has been shown unequivocally to occur de novo to cause a heritable human disease. We have characterized a patient with a de novo nucleic acid transfer from the mitochondrial to the nuclear genome, a transfer that is responsible for a sporadic case of Pallister-Hall syndrome, a condition usually inherited in an autosomal dominant fashion. This mutation, a 72-bp insertion into exon 14 of the GLI3 gene, creates a premature stop codon and predicts a truncated protein product. Both the mechanism and the cause of the mitochondrial-nuclear transfer are unknown. Although the conception of this patient was temporally and geographically associated with high-level radioactive contamination following the Chernobyl accident, this case cannot, on its own, be used to establish a causal relationship between radiation exposure and this rare type of mutation. Thus, for the time being, it must be considered as an intriguing coincidence. Nevertheless, these data serve to demonstrate that de novo mitochondrial-nuclear transfer of nucleic acid is a novel mechanism of human inherited disease.