Fatal Propionic Acidemia in Mice Lacking Propionyl-CoA Carboxylase and Its Rescue by Postnatal, Liver-specific Supplementation via a Transgene

Toru Miyazaki,Toshihiro Ohura,Makio Kobayashi,Yosuke Shigematsu,Seiji Yamaguchi,Yoichi Suzuki,Ikue Hata,Yoko Aoki,Xue Yang,Christina Minjares,Ikuko Haruta,Hirofumi Uto,Yuriko Ito,Urs Müller

doi:10.1074/jbc.m105467200

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.

Highlights

Propionic acidemia (PA) is an inborn error of metabolism caused by the genetic deficiency of propionyl-CoA carboxylase (PCC)
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
A postnatal supplementation of at least 10 –20% of endogenous PCC activity exclusively in the liver prevents the fatal fit of severe ketoacidosis during the newborn and early infant periods

Summary

Introduction

Propionic acidemia (PA) is an inborn error of metabolism caused by the genetic deficiency of propionyl-CoA carboxylase (PCC). To address the potentiality of a tissue-specific gene supplementation as a PA therapy, we generated a transgenic mouse strain expressing PCCA exclusively in the liver and crossbred these two types of mice.

Results

Conclusion