ABCC6 as a target in pseudoxanthoma elasticum

Curr Drug Targets. 2011 May;12(5):671-82. doi: 10.2174/138945011795378612.

Abstract

The ABCC6 gene encodes an organic anion transporter protein, ABCC6/MRP6. Mutations in the gene cause a rare, recessive genetic disease, pseudoxanthoma elasticum, while the loss of one ABCC6 allele is a genetic risk factor in coronary artery disease. We review here the information available on gene structure, evolution as well as the present knowledge on its transcriptional regulation. We give a detailed description of the characteristics of the protein, and analyze the relationship between the distributions of missense disease-causing mutations in the predicted three-dimensional structure of the transporter, which suggests functional importance of the domain-domain interactions. Though neither the physiological function of the protein nor its role in the pathobiology of the diseases are known, a current hypothesis that ABCC6 may be involved in the efflux of one form of Vitamin K from the liver is discussed. Finally, we analyze potential strategies how the gene can be targeted on the transcriptional level to increase protein expression in order to compensate for reduced activity. In addition, pharmacologic correction of trafficking-defect mutants or suppression of stop codon mutations as potential future therapeutic interventions are also reviewed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / metabolism*
  • Alleles
  • Animals
  • Disease Models, Animal
  • Genetic Therapy
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Multidrug Resistance-Associated Proteins / genetics*
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Mutation
  • Pseudoxanthoma Elasticum / genetics*
  • Pseudoxanthoma Elasticum / metabolism
  • Pseudoxanthoma Elasticum / therapy*
  • Vitamin K / chemistry
  • Vitamin K / genetics
  • Vitamin K / metabolism*

Substances

  • ABCC6 protein, human
  • ATP-Binding Cassette Transporters
  • Abcc6 protein, mouse
  • Multidrug Resistance-Associated Proteins
  • Vitamin K