A 500-kb region on chromosome 16p13.1 contains the pseudoxanthoma elasticum locus: high-resolution mapping and genomic structure

Cai, Li; Struk, Berthold; Adams, Mark D.; Ji, Wan; Haaf, Thomas; Kang, Hyung-Lyun; Dho, So Hee; Xu, Xuequn; Ringpfeil, Franziska; Nancarrow, J.K.; Zäch, Stéphanie; Schaen, Lori; Stümm, Markus; Niu, Tianhua; Chung, Joon Yong; Lunze, Karsten; Verrecchia, Bradford; Goldsmith, Lowell A.; Viljoen, Denis; Figuera, Luis E.; Fuchs, W.K.; Lebwohl, Mark; Uitto, Jouni; Richards, Robert I.; Hohl, Daniel; Ramesar, Raj; Callen, David F.; Kim, Ung-Jin; Doggett, Norman A.; Neldner, Kenneth H.; Lindpaintner, Klaus

doi:10.1007/s001090000079

Cited by 63 publications

(49 citation statements)

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“…7, and unpublished data (A.M.C., Ph.D. thesis, Rutgers University, 1991). More recently, two studies provided strong evidence for linkage of both dominantly and recessively inherited forms of PXE to chromosome 16p13.1 by using positional cloning (8,9), and subsequent multicenter collaborative efforts were able to narrow this interval to consist of Ϸ500 kb (10,11). Examination of this interval revealed the presence of four candidate genes (MRP1, MRP6, pM5, and an unknown gene) potentially harboring mutations causing PXE.…”

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confidence: 99%

Pseudoxanthoma elasticum: Mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter

Ringpfeil

Lebwohl

Christiano

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Pseudoxanthoma elasticum (PXE), the prototypic heritable connective tissue disorder affecting the elastic structures in the body, manifests with cutaneous, ophthalmologic, and cardiovascular findings, with considerable morbidity and mortality. The molecular basis of PXE has remained unknown, but the disease locus has recently been mapped to an Ϸ500-kb interval on chromosome 16p13.1, without evidence for locus heterogeneity. In this study, we report pathogenetic mutations in MRP6, a member of the ABC transporter gene family, in eight kindreds with PXE. The mutation detection strategy consisted of heteroduplex scanning of coding sequences in the MRP6 gene, which were amplified by PCR by using genomic DNA as template, followed by direct nucleotide sequencing. A total of 13 mutant MRP6 alleles were disclosed in the eight probands with PXE. These genetic lesions consisted of either single base pair substitutions resulting in missense, nonsense, or splice site mutations, or large deletions resulting in allelic loss of the MRP6 locus. Examination of clinically unaffected family members in four multiplex families identified heterozygous carriers, consistent with an autosomal recessive inheritance pattern. Collectively, identification of mutations in the MRP6 gene provides the basis to examine the pathomechanisms of PXE and allows development of DNA-based carrier detection, prenatal testing, and preimplantation genetic diagnosis in families with a history of this disease.

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mentioning

confidence: 99%

Pseudoxanthoma elasticum: Mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter

Ringpfeil

Lebwohl

Christiano

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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356

249

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“…Several reports have described chromosomal rearrangements, duplications, and sequence repeats that map to regions of chromosome 16 in the vicinity of the MRP1 locus, raising the possibility that either the GCC triplet repeat or the 57-bp direct repeat within the MRP1 5ЈUTR may be present in multiple copies on chromosome 16 (O'Neill et al, 1998;Cai et al, 2000;Ringpfeil et al, 2001). This locus has also clearly undergone a duplication (as evidenced by the presence of the adjacent gene for the MRP1 homolog, MRP6, in an inverted orientation) and is a known area of low abundance repeats (Cai et al, 2000).…”

Section: Evidence For Regulation By Transcription Factors Sp1 and Sp3mentioning

confidence: 99%

Cloning and Characterization of the Murine and Rat mrp1 Promoter Regions

Muredda

Nunoya²,

Burtch-Wright³

et al. 2003

Mol Pharmacol

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The ATP-binding cassette transporter multidrug resistance protein 1 (MRP1) confers resistance to a number of clinically important chemotherapeutic agents. The proximal promoter region of MRP1 is GC-rich and contains binding sites for members of the Sp1 family of trans-acting factors that seem to be important for basal expression. As an approach to searching for other elements that may contribute to expression, we have sequenced and functionally compared the promoters of the murine and rat mrp1 genes with that of the human gene. All three promoters are GC-rich, TATA-less, and CAAT-less. Conservation of sequence between rodent and human promoters is limited to a proximal region of 100 nucleotides containing binding sites for members of the Sp1 family and a putative activator protein-1 element. The 5Ј-untranslated region (UTR) of human MRP1 contains an insertion of approximately 160 nucleotides comprising a GCC-triplet repeat and a GC-rich tandem repeat that is absent from the rodent sequences. Transient transfection analyses demonstrated that the conserved GC-boxes of all three genes are the major determinants of basal activity. Based on electrophoretic mobility shift assays, each GC-box can be bound by Sp1 or Sp3. Unlike the rodent genes, the human MRP1 5ЈUTR also binds Sp1 but not Sp3, and the human promoter retains substantial activity even in the absence of the conserved GC-boxes. Finally, we show that the tumor suppressor protein p53 can repress the human and rodent promoters by a mechanism that is independent of the Sp1 elements.

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“…12 ABCC6 presents a different challenge because major expression is in the hepatocyte basolateral membrane and the protein is mutated in pseudoxanthoma elasticum, a disease characterized by widespread defects in elastic tissue. 13 What the liver secretes into blood, which may regulate elastase and possibly other serine proteases, is not known.…”

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confidence: 99%

Perspective: Five decades of cholestasis research and the brave new world

Arias

2008

Hepatology

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A 500-kb region on chromosome 16p13.1 contains the pseudoxanthoma elasticum locus: high-resolution mapping and genomic structure

Cited by 63 publications

References 20 publications

Pseudoxanthoma elasticum: Mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter

Pseudoxanthoma elasticum: Mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter

Cloning and Characterization of the Murine and Rat mrp1 Promoter Regions

Perspective: Five decades of cholestasis research and the brave new world

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