Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum


Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by calcification of elastic fibres in skin, arteries and retina that results in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency and retinal haemorrhages leading to macular degeneration1,2,3,4,5. PXE is usually found as a sporadic disorder, but examples of both autosomal recessive and autosomal dominant forms of PXE have been observed6. Partial manifestations of the PXE phenotype have also been described in presumed carriers in PXE families7,8. Linkage of both dominant and recessive forms of PXE to a 5-cM domain on chromosome 16p13.1 has been reported (refs 8,9). We have refined this locus to an 820-kb region containing 6 candidate genes10. Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of PXE in a gene encoding a protein associated with multidrug resistance (ABCC6).

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Figure 1: Phenotypic characteristics of PXE in a consanguineous Italian family with PXE.
Figure 2: The identification of an ABCC6 mutation in a consanguineous Italian family with PXE.
Figure 3: Analysis of steady-state levels of ABCC6 mRNA in skin fibroblasts from a PXE patient carrying a homozygous R1141X mutation.
Figure 4: Predicted topology of ABCC6 and the location of six mutations causing PXE.


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We thank the patients and their relatives for cooperation; A. Bergen and his collaborators for sharing unpublished data; A. Varadi for advice regarding topology prediction for ABCC6; F. Boraldi, A. Croce and R. Tiozzo for assistance in preparing cultured skin fibroblasts and isolation of RNA from these cultured cells; and members of the PXE International Research Consortium, particularly P. Terry, N. Doggett and M. Lebwohl, for contributions. This work was supported by NIH grants HL 50665 and EY13019 to C.D.B., a Research Centers in Minority Institutions grant from NCRR (RR03061) to the Pacific Biomedical Research Center of the University of Hawaii and a Telethon-Italy grant (no. 696) to I.P.-R.

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Correspondence to Charles D. Boyd.

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