PMID- 27761413
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 2214-4269 (Print)
IS  - 2214-4269 (Electronic)
IS  - 2214-4269 (Linking)
VI  - 9
DP  - 2016 Dec
TI  - Liver-specific knockout of arginase-1 leads to a profound phenotype similar to 
      inducible whole body arginase-1 deficiency.
PG  - 54-60
AB  - Arginase-1 (Arg1) converts arginine to urea and ornithine in the distal step of 
      the urea cycle in liver. We previously generated a tamoxifen-inducible Arg1 
      deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the 
      whole body and leads to lethality  approximately  2 weeks after gene disruption. Here, we 
      evaluate if liver-selective Arg1 loss is sufficient to recapitulate the phenotype 
      observed in global Arg1 knockout mice, as well as to gauge the effectiveness of 
      gene delivery or hepatocyte transplantation to rescue the phenotype. 
      Liver-selective Arg1 deletion was induced by using an adeno-associated viral 
      (AAV)-thyroxine binding globulin (TBG) promoter-Cre recombinase vector 
      administered to Arg1 "floxed" mice; Arg1(fl/fl) ). An AAV vector expressing an 
      Arg1-enhanced green fluorescent protein (Arg1-eGFP) transgene was used for gene 
      delivery, while intrasplenic injection of wild-type (WT) C57BL/6 hepatocytes 
      after partial hepatectomy was used for cell delivery to "rescue" 
      tamoxifen-treated Arg1-Cre mice. The results indicate that liver-selective loss 
      of Arg1 (> 90% deficient) leads to a phenotype resembling the whole body knockout 
      of Arg1 with lethality  approximately  3 weeks after Cre-induced gene disruption. Delivery of 
      Arg1-eGFP AAV rescues more than half of Arg1 global knockout male mice (survival 
      > 4 months) but a significant proportion still succumb to the enzyme deficiency 
      even though liver expression and enzyme activity of the fusion protein reach 
      levels observed in WT animals. Significant Arg1 enzyme activity from engrafted WT 
      hepatocytes into knockout livers can be achieved but not sufficient for rescuing 
      the lethal phenotype. This raises a conundrum relating to liver-specific 
      expression of Arg1. On the one hand, loss of expression in this organ appears to 
      be both necessary and sufficient to explain the lethal phenotype of the genetic 
      disorder in mice. On the other hand, gene and cell-directed therapies suggest 
      that rescue of extra-hepatic Arg1 expression may also be necessary for disease 
      correction. Further studies are needed in order to illuminate the detailed 
      mechanisms for pathogenesis of Arg1-deficiency.
FAU - Ballantyne, Laurel L
AU  - Ballantyne LL
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      ON, Canada.
FAU - Sin, Yuan Yan
AU  - Sin YY
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      ON, Canada.
FAU - Al-Dirbashi, Osama Y
AU  - Al-Dirbashi OY
AD  - Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, ON, 
      Canada; Faculty of Medicine and Health Sciences, United Arab Emirates University, 
      United Arab Emirates.
FAU - Li, Xinzhi
AU  - Li X
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      ON, Canada.
FAU - Hurlbut, David J
AU  - Hurlbut DJ
AD  - Department of Pathology and Molecular Medicine, Queen's University, Kingston 
      General Hospital, Kingston, ON, Canada.
FAU - Funk, Colin D
AU  - Funk CD
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      ON, Canada.
LA  - eng
PT  - Journal Article
DEP - 20161012
PL  - United States
TA  - Mol Genet Metab Rep
JT  - Molecular genetics and metabolism reports
JID - 101624422
PMC - PMC5065044
OTO - NOTNLM
OT  - AAV, adeno-associated virus
OT  - Arg1, arginase-1
OT  - Arg1-eGFP, arginase-1 enhanced green fluorescent protein
OT  - Arginase
OT  - Gene therapy
OT  - Hepatocyte
OT  - Inducible knockout mice
OT  - Liver
OT  - TBG, thyroxine-binding globulin
OT  - Urea cycle
OT  - WT, wild-type
OT  - gc, genome copies
OT  - ip, intraperitoneal
EDAT- 2016/10/21 06:00
MHDA- 2016/10/21 06:01
PMCR- 2016/10/12
CRDT- 2016/10/21 06:00
PHST- 2016/09/15 00:00 [received]
PHST- 2016/10/05 00:00 [accepted]
PHST- 2016/10/21 06:00 [pubmed]
PHST- 2016/10/21 06:01 [medline]
PHST- 2016/10/21 06:00 [entrez]
PHST- 2016/10/12 00:00 [pmc-release]
AID - S2214-4269(16)30098-2 [pii]
AID - 10.1016/j.ymgmr.2016.10.003 [doi]
PST - epublish
SO  - Mol Genet Metab Rep. 2016 Oct 12;9:54-60. doi: 10.1016/j.ymgmr.2016.10.003. 
      eCollection 2016 Dec.