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. Issue 9 (29th March 2006)

• Record Type: Journal Article
• Authors: Schön, S; Schulz, V; Prante, C; Hendig, D; Szliska, C; Kuhn, J; Kleesiek, K; Götting, C
• Is Part Of: Journal of medical genetics. Volume 43:Issue 9(2006)
• Page Start: 745
• Page End: 749
• Publication Date: 2006-03-29
• Subjects: ABCC6, ATP-binding cassette transporter subfamily C member 6 -- DHPLC, denaturing high performance liquid chromatography -- GAG, glycosaminoglycan -- MRP6, transmembrane transporter protein multidrug resistance-associated protein 6 -- PXE, pseudoxanthoma elasticum -- RFLP, restriction fragment length polymorphism -- SNP, single nucleotide polymorphism -- UTR, untranslated region -- XT, xylosyltransferase (protein) -- XYLT, xylosyltransferase (gene); DHPLC -- polymorphisms -- proteoglycan -- pseudoxanthoma elasticum -- xylosyltransferase; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2006.040972
• Languages: English
• ISSNs: 1468-6244

Abstract

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.