Article Text

Download PDFPDF
Mutation detection in the ABCC6 gene and genotype–phenotype analysis in a large international case series affected by pseudoxanthoma elasticum
  1. Ellen G Pfendner1,2,3,
  2. Olivier M Vanakker4,
  3. Sharon F Terry2,
  4. Sophia Vourthis2,
  5. Patricia E McAndrew1,
  6. Monica R McClain5,
  7. Sarah Fratta2,
  8. Anna-Susan Marais2,7,
  9. Susan Hariri8,
  10. Paul J Coucke4,
  11. Michele Ramsay6,
  12. Denis Viljoen6,
  13. Patrick F Terry2,
  14. Anne De Paepe4,
  15. Jouni Uitto3,
  16. Lionel G Bercovitch2,9
  1. 1GeneDx Inc., Gaithersburg, Maryland, USA
  2. 2PXE International, Washington, DC, USA
  3. 3Department of Dermatology and Cutaneous Biology, Jefferson Medical College and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
  4. 4Ghent University Hospital, Center for Medical Genetics, Ghent, Belgium
  5. 5Institute for Preventive Medicine and Medical Screening, Gray, Maine, USA
  6. 6Division of Human Genetics, National Health Laboratory Service and the University of Witwatersrand, Johannesburg, South Africa
  7. 7University of Cape Town, Cape Town, South Africa
  8. 8Centers for Disease Control and Prevention, Atlanta, Georgia, USA
  9. 9Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
  1. Correspondence to:
 Ellen G Pfendner
 GeneDx Inc., 207 Perry Parkway, Gaithersburg, Maryland 20877, USA; ellen{at}


Background: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6).

Objective: To investigate the mutation spectrum of ABCC6 and possible genotype–phenotype correlations.

Methods: Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype–phenotype correlations were assessed.

Results: In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23–29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype–phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease.

Conclusions: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.

  • ABCC6, ATP-binding cassette family C member 6
  • dHPLC, denaturing high-performance liquid chromatography
  • IC, intracellular domain
  • MRP6, multidrug resistance-associated protein 6
  • NBF, nucleotide-binding fold
  • PTC, premature termination codon
  • PXE, pseudoxanthoma elasticum
  • TM, transmembrane domain
  • pseudoxanthoma elasticum
  • ABC transporters
  • genotype–phenotype correlations
  • heritable skin diseases

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • Published Online First 29 June 2007

  • The first two authors contributed equally to this work.

  • Competing interests: None declared.