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Journal of Molecular Medicine

, Volume 79, Issue 9, pp 536–546 | Cite as

A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum

  • Li Cai
  • Amanda Lumsden
  • Ulf P. Guenther
  • Sarah A. Neldner
  • Stéphanie Zäch
  • Hans Knoblauch
  • Raj Ramesar
  • Daniel Hohl
  • David F. Callen
  • Kenneth H. Neldner
  • Klaus Lindpaintner
  • Robert I. Richards
  • Berthold Struk
Rapid Communication

Abstract

Pseudoxanthoma elasticum (PXE) is an inherited disorder of the elastic tissue with characteristic progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Recently mutations in the ABCC6 gene, encoding a transmembrane transporter protein, were identified as cause of the disease. Surprisingly, sequence and RFLP analysis for exon 9 with primers corresponding to flanking intronic sequence in diseased and haplotype negative members from all of our families and in a control population revealed either a homozygous or heterozygous state for the Q378X (1132CT) nonsense mutation in all individuals. With the publication of the genomic structure of the PXE locus we had identified the starting point of a large genomic segmental duplication within the locus in the cytogenetic interval defined by the Cy19 and Cy185 somatic cell hybrid breakpoints on chromosome 16p13.1. By means of somatic cell hybrid mapping we located this starting point telomeric to exon 10 of ABCC6. The duplication, however, does not include exon 10, but exons 1–9. These findings suggest that one or several copies of an ABCC6 pseudogene (ψABCC6) lie within this large segmental duplication. At least one copy contains exons 1–9 and maps to the chromosomal interval defined by the Cy163 and Cy11 breakpoints. Either this copy and/or an additional copy of ψABCC6 within Cy19-Cy183 carries the Q378X mutation that masks the correct identification of this nonsense mutation as being causative in pseudoxanthoma elasticum. Long-range PCR of exon 9 starting from sequence outside the genomic replication circumvents interference from the ψABCC6 DNA sequences and demonstrates that the Q378X mutation in the ABCC6 gene is associated with PXE in some families. These findings lead us to propose that gene conversion mechanisms from ψABCC6 to ABCC6 play a functional role in mutations causing PXE.

Pseudoxanthoma elasticum ATP-binding cassette proteins ABCC6 Pseudogene Gene conversion 

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Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • Li Cai
    • 1
  • Amanda Lumsden
    • 2
  • Ulf P. Guenther
    • 7
  • Sarah A. Neldner
    • 1
  • Stéphanie Zäch
    • 3
  • Hans Knoblauch
    • 4
  • Raj Ramesar
    • 5
  • Daniel Hohl
    • 3
  • David F. Callen
    • 2
  • Kenneth H. Neldner
    • 6
  • Klaus Lindpaintner
    • 1
  • Robert I. Richards
    • 2
  • Berthold Struk
    • 1
  1. 1.Endocrinology and Hypertension Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115USA
  2. 2.Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, 71 King William Road, North Adelaide S.A. 5006Australia
  3. 3.Department of Dermatology, University of Lausanne, 1011 LausanneSwitzerland
  4. 4.Institute of Medical Genetics, Humboldt University, BerlinGermany
  5. 5.Department of Human Genetics, Medical School, University of Cape Town, Observatory 7925South Africa
  6. 6.Department of Dermatology, Texas Tech University Health Sciences Center, Lubbock, TX 79430USA
  7. 7.Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13093 BerlinGermany

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