title: Fatal propionic acidemia in mice lacking propionyl-CoA carboxylase and its rescue by postnatal, liver-specific supplementation via a transgene.
abstract: Propionic acidemia (PA) is an inborn error of metabolism caused by the genetic deficiency of propionyl-CoA carboxylase (PCC). By disrupting the alpha-subunit 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-specific 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). Interestingly, SAP(+)PCCA(-/-) mice, in which the transgene expression increased after the late infant period, continued to grow normally while mice harboring a persistent low level of PCC died in the late infant period due to severe ketoacidosis, clearly suggesting the requirement of increased PCC supplementation in proportion to the animal growth. Based on these results, we propose a two-step strategy to achieve an efficient PA prevention in human 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.
authors.affiliation: Center for Immunology, The University of Texas Southwestern Medical Center, Dallas Texas 75390-9093, USA. Toru.Miyazaki@UTSouthwestern.edu
authors.forename: T
authors.initials: T
authors.lastname: Miyazaki
authors.forename: T
authors.initials: T
authors.lastname: Ohura
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Shigematsu
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: I
authors.initials: I
authors.lastname: Hata
authors.forename: Y
authors.initials: Y
authors.lastname: Aoki
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: C
authors.initials: C
authors.lastname: Minjares
authors.forename: I
authors.initials: I
authors.lastname: Haruta
authors.forename: H
authors.initials: H
authors.lastname: Uto
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.forename: U
authors.initials: U
authors.lastname: Müller
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000008:administration & dosage / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008661:Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D043586:Methylmalonyl-CoA Decarboxylase; D051379:Mice; D018345:Mice, Knockout; D011422:Propionates / Q000378:metabolism*; D019076:Transgenes
chemical_list: D011422:Propionates; D002262:Carboxy-Lyases; D043586:Methylmalonyl-CoA Decarboxylase; C029658:propionic acid