Indeed, the current data favor a model in which defects in the resolution of transcription-blocking structures (e.g. DNA damage or G-quadraplexes) within the nuclear genome lead to PARP1 hyper-activation and consequent mitochondrial dysfunction, cellular events that likely underlie the clinical pathologies associated with CS and possibly other genetic disorders21,22. The gene discussed is PARP1; the disease is Cowden syndrome 1.