RGD Reference Report - Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum. - Rat Genome Database

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Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum.

Authors: Li, Qiaoli  Kingman, Joshua  van de Wetering, Koen  Tannouri, Sami  Sundberg, John P  Uitto, Jouni 
Citation: Li Q, etal., J Invest Dermatol. 2017 May;137(5):1025-1032. doi: 10.1016/j.jid.2016.11.042. Epub 2017 Jan 19.
RGD ID: 13792593
Pubmed: PMID:28111129   (View Abstract at PubMed)
PMCID: PMC6251403   (View Article at PubMed Central)
DOI: DOI:10.1016/j.jid.2016.11.042   (Journal Full-text)

Pseudoxanthoma elasticum, a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene primarily expressed in the liver and the kidneys. The fundamental question on pathogenesis of pseudoxanthoma elasticum, whether lack of ABCC6 expression in liver or kidney is the primary site of molecular pathology in peripheral tissues, has not been addressed. We generated a series of Abcc6-/- rats as models of pseudoxanthoma elasticum depicting ectopic mineralization in the skin, eyes, and the arterial blood vessels. Plasma inorganic pyrophosphate (PPi) level was reduced (<30%) in the Abcc6-/- rats leading to a lowered PPi/inorganic phosphate plasma ratio. In situ liver and kidney perfusions were performed to determine the relative contribution of these organs to PPi levels in circulation. PPi levels in the perfusates both in the liver and kidney of Abcc6-/- rats were significantly reduced, but the PPi levels in the liver perfusates of wild-type rats were 10-fold higher than that in the kidney perfusates. These observations suggest a critical role of hepatic ABCC6 in contributing to plasma PPi levels, identifying liver as a target of molecular correction to counteract ectopic mineralization in pseudoxanthoma elasticum.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pseudoxanthoma elasticum  ISOAbcc6 (Rattus norvegicus)13792593; 13792593 RGD 
pseudoxanthoma elasticum  IMP 13792593; 13792593; 13792593; 13792593; 13792593; 13792593 RGD 
pseudoxanthoma elasticum MODEL: spontaneousIMP 13792593 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
inorganic diphosphate transport involved_inIDA 13792593PMID:28111129UniProt 
intracellular phosphate ion homeostasis involved_inIMP 13792593PMID:28111129UniProt 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
basolateral plasma membrane  IDA 13792593MMO:0000662RGD 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
inorganic diphosphate transmembrane transporter activity enablesIDA 13792593PMID:28111129UniProt 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
increased circulating phosphate level  IAGP 13792593; 13792593; 13792593 RGD 

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Objects Annotated

Genes (Rattus norvegicus)
Abcc6  (ATP binding cassette subfamily C member 6)
Abcc6em2Qlju  (ATP-binding cassette, subfamily C (CFTR/MRP), member 6; zinc finger nuclease induced mutant 2, Qiaoli Li)
Abcc6em3Qlju  (ATP-binding cassette, subfamily C (CFTR/MRP), member 6; zinc finger nuclease induced mutant 3, Qiaoli Li)
Abcc6em4Qlju  (ATP-binding cassette, subfamily C (CFTR/MRP), member 6; zinc finger nuclease induced mutant 4, Qiaoli Li)

Genes (Mus musculus)
Abcc6  (ATP-binding cassette, sub-family C member 6)

Genes (Homo sapiens)
ABCC6  (ATP binding cassette subfamily C member 6)

Objects referenced in this article
Gene Abcc6em1Qlju ATP-binding cassette, subfamily C (CFTR/MRP), member 6; zinc finger nuclease induced mutant 1, Qiaoli Li Rattus norvegicus
Gene Abcc6em5Qlju ATP-binding cassette, subfamily C (CFTR/MRP), member 6; zinc finger nuclease induced mutant 5, Qiaoli Li Rattus norvegicus
Strain SD-Abcc6em1Qlju-/- null Rattus norvegicus
Strain SD-Abcc6em2Qlju+/+ null Rattus norvegicus
Strain SD-Abcc6em2Qlju+/- null Rattus norvegicus
Strain SD-Abcc6em5Qlju-/- null Rattus norvegicus

Additional Information