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
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
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DOI：
10.1136/jmg.2006.040972
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发表时间：
2006-09-01
影响因子：
4
通讯作者：
Goetting, C.
中科院分区：
文献类型：
--
作者：
Schoen, S.;Schulz, V.;Goetting, C.
背景：弹性假黄瘤是一种由ABCC6基因突变引起的遗传性结缔组织疾病。弹力纤维的碎裂和蛋白多糖的沉积导致高度可变的临床图景。蛋白多糖代谢的改变表明，这一途径中的酶在PXE的严重性中起到遗传辅助因素的作用。因此，我们建议将编码木糖转移酶I(XT-I)的XYLT基因作为蛋白多糖生物合成中的链起始酶，并将高度同源性的XT-II基因作为潜在的候选基因。方法：采用变性高效液相色谱法对65例德国PXE患者的所有XYLT外显子进行筛查，并分析其变异对临床特征的影响。错义变异p.A115S(XT-I)与较高的血清XT活性相关(P=0.005)。氨基酸取代p.T801R(XT-II；c.2402C.在确诊时年龄在30岁以下的患者中，皮损的发生率显著更高(43%vs26%；p=0.04)；具有这种变异的所有pxe患者都有皮肤皮损，而野生型患者中只有75%(p=0.002)。XYLT-II基因c.166G>；A、c.1569C>；T和c.2402C>；G在器官受累程度较高的患者中出现频率较高(分别为p=0.04、p=0.01和p=0.02)。结论：首次发现XYLT-II基因变异是PXE严重程度的遗传辅助因素。此外，A115S(XT-I)交换型患者的XT活性较高，表明该多态是增加细胞外基质重塑的潜在标记物。
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.