Fatal propionic acidemia in mice lacking Propionyl-CoA carboxylase and itsrescue by postnatal, liver-specific supplementation via a transgene

Propionic acidemia (PA) is an inborn error of metabolism caused by the gene tic deficiency of propionyl-CoA carboxylase (PCC). By disrupting the a-subu nit gene of PCC, we created a mouse model of PA (PCCA(-/-)), which died in 24-36 h after birth due to accelerated ketoacidosis. A postnatal, liver-spe cific PCC expression via a transgene in a far lower level than that in wild -type liver, allowed PCCA(-/-) mice to survive the newborn and early infant periods, preventing a lethal fit of ketoacidosis (SAP(+)PCCA(-/-) mice). I nterestingly, SAP(+)PCCA(-/-) mice, in which the transgene expression incre ased after the late infant period, continued to grow normally while mice ha rboring a persistent low level of PCC died in the late infant period due to severe ketoacidosis, clearly suggesting the requirement of increased PCC s upplementation in proportion to the animal growth. Based on these results, we propose a two-step strategy to achieve an efficient PA prevention in hum an patients: a partial PCC supplementation in the liver during the newborn and early infant periods, followed by a larger amount of supplementation in the late infant period.