Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in ABCC6 cause pseudoxanthoma elasticum

Abstract

Pseudoxanthoma elasticum (PXE) is a heritable disorder of the connective tissue. PXE patients frequently experience visual field loss and skin lesions, and occasionally cardiovascular complications1,2,3,4. Histopathological findings reveal calcification of the elastic fibres and abnormalities of the collagen fibrils5. Most PXE patients are sporadic, but autosomal recessive and dominant inheritance are also observed6,7. We previously localized the PXE gene to chromosome 16p13.1 (refs 8,9) and constructed a physical map10. Here we describe homozygosity mapping in five PXE families and the detection of deletions or mutations in ABCC6 (formerly MRP6) associated with all genetic forms of PXE in seven patients or families.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Clinical phenotype, segregation and mutation analysis in a large arPXE pedigree (P-12).
Figure 2: Overview of the positional identification of the PXE gene.
Figure 3: RT–PCR of ABCC6 RNA in various tissues.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Yap, E.Y., Gleaton, M.S. & Buettner, H. Visual loss associated with pseudoxanthoma elasticum. Retina 12, 315–319 (1992).

    Article  CAS  Google Scholar 

  2. Christiano, A.M. & Uitto, J. Molecular pathology of the elastic fibers. J. Invest. Dermatol. 103, 53S–57S (1994).

    Article  Google Scholar 

  3. Mendelsohn, G., Bulkley, B.H. & Hutchins, G.M. Cardiovascular manifestations of pseudoxanthoma elasticum. Arch. Pathol. Lab. Med. 102, 298–302 (1978).

    CAS  PubMed  Google Scholar 

  4. Lebwohl, M. et al. Abnormalities of connective tissue components in lesional and non-lesional tissue of patients with pseudoxanthoma elasticum. Arch. Dermatol. Res. 285, 121–126 (1993).

    Article  CAS  Google Scholar 

  5. Hausser, I. & Anton-Lamprecht, I. Early preclinical diagnosis of dominant pseudoxanthoma elasticum by specific ultrastructural changes of dermal elastic and collagen tissue in a family at risk. Hum. Genet. 87, 693–700 (1991).

    Article  CAS  Google Scholar 

  6. Christiano, A.M., Lebwohl, M.B., Boyd, C.D. & Uitto, J. Workshop on pseudoxanthoma elasticum: molecular biology and pathology of the elastic fibres. Jefferson Medical College, Philadelphia, Pennsylvania, June 10, 1992. J. Invest. Dermatol. 99, 660–663 (1992).

    Article  CAS  Google Scholar 

  7. Lebwohl, M. et al. Classification of pseudoxanthoma elasticum: report of a consensus conference. J. Am. Acad. Dermatol. 30, 103–107 (1994).

    Article  CAS  Google Scholar 

  8. van Soest, S. et al. A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1. Genome Res. 7, 830–834 (1997).

    Article  CAS  Google Scholar 

  9. Struk, B., Neldner, K.H., Rao, V.S., St Jean, P. & Lindpaintner, K. Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1. Hum. Mol. Genet. 6, 1823–1828 (1997).

    Article  CAS  Google Scholar 

  10. Le Saux, O. et al. Pseudoxanthoma elasticum maps to an 820 kb region of the p13.1 region of chromosome 16. Genomics 62, 1–10 (1999).

    Article  CAS  Google Scholar 

  11. Hipfner, D.R., Deeley, R.G. & Cole, S.P. Structural, mechanistic and clinical aspects of MRP1. Biochim. Biophys. Acta 6, 359–376 (1999).

    Article  Google Scholar 

  12. Kool, M., van der Linden, M., de Haas, M., Baas, F. & Borst, P. Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Cancer Res. 59, 175–182 (1999).

    CAS  PubMed  Google Scholar 

  13. Allikmets, R., Gerrard, B., Hutchinson, A. & Dean, M. Characterisation of the human ABC superfamily: Isolation and mapping of 21 new genes using the expressed sequence tags database. Hum. Mol. Genet. 10, 1649–1655 (1996).

    Article  Google Scholar 

  14. Hoogendijk, J.E. et al. De novo mutations in hereditary motor and sensory neuropathy type 1. Lancet 339, 1081–1082 (1992).

    Article  CAS  Google Scholar 

  15. Leeds, P. et al. The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. Genes Dev. 5, 2303–2314 (1991).

    Article  CAS  Google Scholar 

  16. Culbertson, M.R. RNA surveillance: unforeseen consequences for gene expression, inherited genetic disorders and cancer. Trends Genet. 15, 74–80 (1999).

    Article  CAS  Google Scholar 

  17. Christiano, A.M., McGrath, J.A., Tan, K.C. & Uitto, J. Glycine substitutions in the triple-helical region of type VII collagen result in a spectrum of dystrophic epidermolysis bullosa phenotypes and patterns of inheritance. Am. J. Hum. Genet. 58, 671–681 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Van Ommen, G.J.B. Merging autosomal dominance and recessivity. Am. J. Hum. Genet. 41, 689–691 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Van Soest, S., Westerveld, A, de Jong, P.T.V.M., Bleeker-Wagemakers, E.M. & Bergen, A.A.B. Retinitis pigmentosa: defined from a molecular point of view. Surv. Ophthalmol. 43, 321–334 (1999).

    Article  CAS  Google Scholar 

  20. Dietz, H.C. et al. The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259, 680–683 (1993).

    Article  CAS  Google Scholar 

  21. Dietz, H.C. & Kendzior, R.J. Jr Maintenance of an open reading frame as an additional level of scrutiny during splice site selection. Nature Genet. 8, 183–188 (1994).

    Article  CAS  Google Scholar 

  22. Bergen, A.A.B. et al. Detection of a new submicroscopic Norrie disease deletion interval with a novel DNA probe isolated by differential Alu PCR fingerprint cloning. Cytogenet. Cell Genet. 62, 231–235 (1993).

    Article  CAS  Google Scholar 

  23. Dauwerse, J.G. et al. Cloning the breakpoint cluster region of the inv (16) in acute nonlymphocytic leukemia M4 Eo. Hum. Mol. Genet. 2, 1527–1534 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Boyd for sharing unpublished data; R.J. Oostra, R. Hennekam, N.T. Tijmes, P. van den Berg, L. Kornet, J.R.M. Cruysberg and F. Steijlen for examination of patients; F. Cremers, C. de Vries and J. Wijnholds for RNA of different tissues; M. Lettink, M.T. van Meegen and D. Schildknegt for technical assistance; and the PXE families for their support. This study was supported by a ANVtVB-grant to A.A.B.B.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Arthur A.B. Bergen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bergen, A., Plomp, A., Schuurman, E. et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet 25, 228–231 (2000). https://doi.org/10.1038/76109

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/76109

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing