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New ABCC6 gene mutations in German pseudoxanthoma elasticum patients

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Abstract

Pseudoxanthoma elasticum (PXE; OMIM 177850 and 264800) is a rare heritable disorder of the connective tissue affecting the extracellular matrix of the skin, eyes, gastrointestinal system, and cardiovascular system. It has recently been found that mutations in the ABCC6 gene encoding the multidrug resistance-associated protein (MRP) 6 cause PXE. This study examined novel mutations in the ABCC6 gene in our cohort of 76 German PXE patients and 54 unaffected or not yet affected relatives with a view to expanding the known mutational spectrum of the gene. Mutational analysis was performed using denaturing high-performance liquid chromatography and direct sequencing. The mutational screening revealed a total of 22 different ABCC6 sequence variations. We identified seven novel and four previously described PXE-associated mutations as well as eight novel neutral ABCC6 sequence variants. The new PXE-associated mutations included five missense mutations, one single base pair deletion, and one larger out-of-frame deletion. We suspect that the novel missense mutations lead to an impaired function of MRP6. Both deletions are predicted to result in a dysfunctional MRP6 protein. The seven new ABCC6 mutations were not present in 200 alleles from healthy blood donors which served as a control cohort. Most of the PXE patients who were found to carry PXE-causing ABCC6 mutations were assumed to manifest the PXE phenotype because of a compound heterozygous genotype. However, a genotype-phenotype correlation could not be established for the detected ABCC6 mutations. In summary, our data give a further insight into the spectrum of ABCC6 mutations in PXE patients.

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Abbreviations

ABC :

ATP-binding cassette

DHPLC :

Denaturing high-performance liquid chromatography

MRP :

Multidrug resistance-associated protein

NBF :

Nucleotide binding fold

PCR :

Polymerase chain reaction

PXE :

Pseudoxanthoma elasticum

TMD :

Transmembrane-spanning domain

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Acknowledgements

We thank Alexandra Adam and Marlen Ewald for excellent technical assistance and Grainne Delany for linguistic advice. We are very grateful to all the PXE patients and their relatives, whose cooperation made this study possible. Furthermore, we thank Peter Hof, Chairman of the Selbsthilfegruppe für PXE-Erkrankte Deutschlands 1999 e.V., and the members of the clinical ambulance for PXE at the Bethesda Hospital in Freudenberg, Germany.

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Authors and Affiliations

  1. Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik , der Ruhr-Universität Bochum, 32545, Bad Oeynhausen, Germany

    Doris Hendig, Veronika Schulz, Christian Götting & Knut Kleesiek

  2. Dermatologische Klinik, Krankenhaus Bethesda, Freudenberg, Germany

    Jutta Eichgrün & Christiane Szliska

Authors
  1. Doris Hendig
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  2. Veronika Schulz
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  3. Jutta Eichgrün
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  4. Christiane Szliska
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  5. Christian Götting
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  6. Knut Kleesiek
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Correspondence to Christian Götting.

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Hendig, D., Schulz, V., Eichgrün, J. et al. New ABCC6 gene mutations in German pseudoxanthoma elasticum patients. J Mol Med 83, 140–147 (2005). https://doi.org/10.1007/s00109-004-0588-2

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  • DOI: https://doi.org/10.1007/s00109-004-0588-2

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