PMID- 10485908
OWN - NLM
STAT- MEDLINE
DCOM- 19991014
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 19
DP  - 1999 Sep 14
TI  - Targeted gene disruption reveals an essential role for ceruloplasmin in cellular 
      iron efflux.
PG  - 10812-7
AB  - Aceruloplasminemia is an autosomal recessive disorder of iron metabolism.
      Affected individuals evidence iron accumulation in tissue parenchyma in
      association with absent serum ceruloplasmin. Genetic studies of such patients
      reveal inherited mutations in the ceruloplasmin gene. To elucidate the role of
      ceruloplasmin in iron homeostasis, we created an animal model of
      aceruloplasminemia by disrupting the murine ceruloplasmin (Cp) gene. Although
      normal at birth, Cp(-/-) mice demonstrate progressive accumulation of iron such
      that by one year of age all animals have a prominent elevation in serum ferritin 
      and a 3- to 6-fold increase in the iron content of the liver and spleen.
      Histological analysis of affected tissues in these mice shows abundant iron
      stores within reticuloendothelial cells and hepatocytes. Ferrokinetic studies in 
      Cp(+/+) and Cp(-/-) mice reveal equivalent rates of iron absorption and plasma
      iron turnover, suggesting that iron accumulation results from altered
      compartmentalization within the iron cycle. Consistent with this concept, Cp(-/-)
      mice showed no abnormalities in cellular iron uptake but a striking impairment in
      the movement of iron out of reticuloendothelial cells and hepatocytes. Our
      findings reveal an essential physiologic role for ceruloplasmin in determining
      the rate of iron efflux from cells with mobilizable iron stores.
FAU - Harris, Z L
AU  - Harris ZL
AD  - Edward Mallinckrodt Department of Pediatrics, Washington University School of
      Medicine, St. Louis, MO 63110, USA.
FAU - Durley, A P
AU  - Durley AP
FAU - Man, T K
AU  - Man TK
FAU - Gitlin, J D
AU  - Gitlin JD
LA  - eng
GR  - DK02464/DK/NIDDK NIH HHS/United States
GR  - HD33688/HD/NICHD NIH HHS/United States
GR  - HL41536/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Apoproteins)
RN  - 0 (apoceruloplasmin)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.16.3.1 (Ceruloplasmin)
SB  - IM
MH  - Animals
MH  - Apoproteins/metabolism
MH  - Ceruloplasmin/deficiency/*genetics/metabolism/*physiology
MH  - Disease Models, Animal
MH  - Homeostasis
MH  - Iron/blood/*metabolism/pharmacokinetics
MH  - Liver/anatomy & histology/metabolism
MH  - Metal Metabolism, Inborn Errors/genetics/metabolism
MH  - Mice
MH  - Models, Genetic
MH  - Mutagenesis, Insertional
MH  - Neurodegenerative Diseases/genetics/metabolism
MH  - Phenotype
MH  - Spleen/anatomy & histology/metabolism
MH  - Time Factors
PMC - PMC17965
EDAT- 1999/09/15 00:00
MHDA- 1999/09/15 00:01
CRDT- 1999/09/15 00:00
PHST- 1999/09/15 00:00 [pubmed]
PHST- 1999/09/15 00:01 [medline]
PHST- 1999/09/15 00:00 [entrez]
AID - 10.1073/pnas.96.19.10812 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10812-7. doi:
      10.1073/pnas.96.19.10812.