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

Sylvia Schön ¹, Veronika Schulz ¹, Christian Prante ¹, Doris Hendig ¹, Christiane Szliska ², Joachim Juhn ¹, Knut Kleesiek ¹ and Christian Götting ^3*

¹ Herz- und Diabeteszentrum NRW, Institut für Laboratoriums- und Transfusionsmedizin
² Dermatologische Klinik, Krankenhaus Bethesda
³ Laboratoriums- und Transfusionsmedizin

^* To whom correspondence should be addressed. E-mail: cgoetting{at}hdz-nrw.de.

Accepted 6 March 2006

Abstract

Background: Pseudoxanthoma elasticum (PXE) is a heritable connective tissue disorder caused by mutations in the ABCC6 gene. The fragmentation of elastic fibres and the deposition of proteoglycans result in a highly variable clinical picture. The altered proteoglycan metabolism lets us suppose 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 activities (p=0.005). The amino acid substitution p.T801R (XT-II; c.2402C>G) occurs with a significantly higher frequency in patients with an age of diagnosis under 30 years (43% vs. 26%; p=0.04) and all PXE patients with this variation suffer from skin lesions, whereas only 75% of the wildtype patients show them (p=0.002). We detected that c.166G>A, c.1569C>T and c.2402C>G in the XYLTII gene are more frequent in patients with a higher organ involvement (p=0.04; p=0.01; p=0.02).

Conclusions: Here we could 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 activities in patients with the exchange p.A115S (XT-I) indicates this polymorphism to be a potential marker for the increased remodeling of the extracellular matrix.

Keywords: DHPLC, Pseudoxanthoma elasticum, polymorphisms, proteoglycan, xylosyltransferase

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