ORIGINAL ARTICLE

Mutation detection in the ABCC6 gene and genotype–phenotype analysis in a large international case series affected by pseudoxanthoma elasticum

Ellen G Pfendner^1,2,3, Olivier M Vanakker⁴, Sharon F Terry², Sophia Vourthis², Patricia E McAndrew¹, Monica R McClain⁵, Sarah Fratta², Anna-Susan Marais^2,7, Susan Hariri⁸, Paul J Coucke⁴, Michele Ramsay⁶, Denis Viljoen⁶, Patrick F Terry², Anne De Paepe⁴, Jouni Uitto³, Lionel G Bercovitch^2,9

¹ GeneDx Inc., Gaithersburg, Maryland, USA
² PXE International, Washington, DC, USA
³ Department of Dermatology and Cutaneous Biology, Jefferson Medical College and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
⁴ Ghent University Hospital, Center for Medical Genetics, Ghent, Belgium
⁵ Institute for Preventive Medicine and Medical Screening, Gray, Maine, USA
⁶ Division of Human Genetics, National Health Laboratory Service and the University of Witwatersrand, Johannesburg, South Africa
⁷ University of Cape Town, Cape Town, South Africa
⁸ Centers for Disease Control and Prevention, Atlanta, Georgia, USA
⁹ Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA

Correspondence to:
Ellen G Pfendner
GeneDx Inc., 207 Perry Parkway, Gaithersburg, Maryland 20877, USA; ellen{at}genedx.com

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.

Abbreviations: 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

Keywords: pseudoxanthoma elasticum; ABC transporters; genotype–phenotype correlations; heritable skin diseases

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Li, Q., Schurgers, L. J., Smith, A. C.M., Tsokos, M., Uitto, J., Cowen, E. W. (2009). Co-Existent Pseudoxanthoma Elasticum and Vitamin K-Dependent Coagulation Factor Deficiency: Compound Heterozygosity for Mutations in the GGCX Gene. Am. J. Pathol. 174: 534-540 [Abstract] [Full Text]  
• Paumi, C. M., Chuk, M., Chevelev, I., Stagljar, I., Michaelis, S. (2008). Negative Regulation of the Yeast ABC Transporter Ycf1p by Phosphorylation within Its N-terminal Extension. J. Biol. Chem. 283: 27079-27088 [Abstract] [Full Text]  
• von Beckerath, O., Gaa, J., von Mohrenfels, C. W., von Beckerath, N. (2008). Intermittent Claudication in a 28-Year-Old Man With Pseudoxanthoma Elasticum. Circulation 118: 102-104 [Full Text]