Polymorphisms in the xylosyltransferase genes cause higher serum XT-I activity in patients with pseudoxanthoma elasticum (PXE) and are involved in a severe disease course - PubMed (original) (raw)

Polymorphisms in the xylosyltransferase genes cause higher serum XT-I activity in patients with pseudoxanthoma elasticum (PXE) and are involved in a severe disease course

S Schön et al. J Med Genet. 2006 Sep.

Abstract

Background: Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in the ABCC6 gene. Fragmentation of elastic fibres and deposition of proteoglycans result in a highly variable clinical picture. The altered proteoglycan metabolism suggests that enzymes from this pathway function as genetic co-factors in the severity of PXE. Therefore, we propose the XYLT genes encoding xylosyltransferase I (XT-I) as the chain-initiating enzyme in the biosynthesis of proteoglycans and the highly homologous XT-II as potential candidate genes.

Methods: We screened all XYLT exons in 65 German PXE patients using denaturing high performance liquid chromatography and analysed the influence of the variations on clinical characteristics.

Results: We identified 22 variations in the XYLT genes. The missense variation p.A115S (XT-I) is associated with higher serum XT activity (p = 0.005). The amino acid substitution p.T801R (XT-II; c.2402C>G) occurs with significantly higher frequency in patients under 30 years of age at diagnosis (43% v 26%; p = 0.04); all PXE patients with this variation suffer from skin lesions compared to only 75% of the wild type patients (p = 0.002). c.166G>A, c.1569C>T, and c.2402C>G in the XYLT-II gene were found to be more frequent in patients with higher organ involvement (p = 0.04, p = 0.01, and p = 0.02, respectively).

Conclusions: Here we show for the first time that variations in the XYLT-II gene are genetic co-factors in the severity of PXE. Furthermore, the higher XT activity in patients with the exchange p.A115S (XT-I) indicates that this polymorphism is a potential marker for increased remodelling of the extracellular matrix.

PubMed Disclaimer

Conflict of interest statement

Competing interests: none declared

Figures

None

Similar articles

Cited by

References

    1. Neldner K H. Pseudoxanthoma elasticum. Int J Dermatol 19882798–100. - PubMed
    1. Bergen A A, Plomp A S, Schuurman E J, Terry S, Breuning M, Dauwerse H, Swart J, Kool M, van Soest S, Baas F, ten Brink J B, de Jong P T V M. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet 200025228–231. - PubMed
    1. Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D, Pasquali‐Ronchetti I, Pope F M, Richards A, Terry S, Bercovitch L, de Paepe A, Boyd C D. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet 200025223–227. - PubMed
    1. Ringpfeil F, Lebwohl M G, Christiano A M, Uitto J. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP‐binding cassette (ABC) transporter. Proc Natl Acad Sci U S A 2000976001–6006. - PMC - PubMed
    1. Struk B, Cai L, Zach S, Ji W, Chung J, Lumsden A, Stumm M, Huber M, Schaen L, Kim C A, Goldsmith L A, Viljoen D, Figuera L E, Fuchs W, Munier F, Ramesar R, Hohl D, Richards R, Neldner K H, Lindpaintner K. Mutations of the gene encoding the transmembrane transporter protein ABC‐C6 cause pseudoxanthoma elasticum. J Mol Med 200078282–286. - PubMed

MeSH terms

Substances

LinkOut - more resources