Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations

Tamás Arányi, Caroline Bacquet, Hugues de Boussac, Marcin Ratajewski, Viola Pomozi, Krisztina Fülöp, Christopher N. Brampton, Lukasz Pulaski, Olivier Le Saux, András Váradi

Research output: Contribution to journalReview article

5 Citations (Scopus)


The human ATP-binding cassette family C member 6 (ABCC6) gene encodes an ABC transporter protein expressed primarily in the liver and to a lesser extent in the kidneys and the intestines. We review here the mechanisms of this restricted tissue-specific expression and the role of hepatocyte nuclear factor 4α which is responsible forthe expression pattern. Detailed analyses uncovered further regulators of the expression of the gene pointing to an intronic primate-specific regulator region, an activator of the expression of the gene by binding CCAAT/enhancer-binding protein beta, which interacts with other proteins acting in the proximal promoter. This regulatory network is affected by various environmental stimuli including oxidative stress and the extracellular signal-regulated protein kinases 1 and 2 pathway. We also review here the structural and functional consequences of disease-causing missense mutations of ABCC6. A significant clustering of the missense disease-causing mutations was found at the domain-domain interfaces. This clustering means that the domain contacts are much less permissive to amino acid replacements than the rest of the protein. We summarize the experimental methods resulting in the identification of mutants with preserved transport activity but failure in intracellular targeting. These mutants are candidates for functional rescue by chemical chaperons. The results of such research can provide the basis of future allele-specific therapy of ABCC6-mediated disorders like pseudoxanthoma elasticum or the generalized arterial calcification in infancy.

Original languageEnglish
Article numberArticle 27
JournalFrontiers in Genetics
Issue numberMAR
Publication statusPublished - Apr 18 2013



  • 4-phenyl-butyrate
  • Abcc6
  • C/EBPβ
  • Calcification
  • Generalized arterial calcification in infancy
  • HNF4α
  • Pseudoxanthoma elasticum

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

Cite this

Arányi, T., Bacquet, C., de Boussac, H., Ratajewski, M., Pomozi, V., Fülöp, K., Brampton, C. N., Pulaski, L., Le Saux, O., & Váradi, A. (2013). Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations. Frontiers in Genetics, 4(MAR), [Article 27].