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

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.

Pseudoxanthoma elasticum: Wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6

“…Previously, three variations in the gene for xylosyltransferase II were found, which were associated with a more severe phenotype in patients with PXE. 28 Xylosyltransferase II plays a role in proteoglycan metabolism. In another study, promoter polymorphisms of the SPP1 gene were significantly more often present in patients with PXE than in controls, so that it was suggested that SPP1 is a modifier gene for PXE.…”

Pseudoxanthoma Elasticum: Genetic Variations in Antioxidant Genes Are Risk Factors for Early Disease Onset

“…These findings led to the assumption that other genes and environmental factors might contribute to the expression and severity of PXE (15 ). Our group has already demonstrated that polymorphisms in genes encoding xylosyltransferases are associated with a severe disease course (16 ). Recently, PXE fibroblasts were shown to undergo mild chronic oxidative stress (17 ).…”

Modifier genes in pseudoxanthoma elasticum: novel insights from the Ggcx mouse model

“…An association study suggested that polymorphisms in the SPP1 promoter contribute to PXE susceptibility [23]. Genes involved in the response to oxidative stress have also been implicated in PXE: polymorphisms in the xylosyltransferase genes (XT) leading to higher serum XT activity were found to correlate with disease severity in patients with PXE [24]; association studies have suggested that catalase, superoxide dismutase 2, and glutathione peroxidase 1 are risk factors for early disease onset [25]. More recently, VEGF gene polymorphisms were found to be associated with early and severe retinopathy in PXE [26].…”