Elevated xylosyltransferase I activities in pseudoxanthoma elasticum (PXE) patients as a marker of stimulated proteoglycan biosynthesis

Abstract

Pseudoxanthoma elasticum (PXE) is a hereditary disorder of the connective tissue characterized by extracellular matrix alterations with elastin fragmentation and excessive proteoglycan deposition. Xylosyltransferase I (XT-I, E.C. 2.4.2.26) is the initial enzyme in the biosynthesis of the glycosaminoglycan chains in proteoglycans and has been shown to be a marker of tissue remodeling processes. Here, we investigated for the first time serum XT-I activities in a large cohort of German PXE patients and their unaffected relatives. XT-I activities were measured in serum samples from 113 Caucasian patients with PXE and 103 unaffected first-degree family members. The occurrence of the frequent ABCC6 gene mutation c.3421C>T (R1141X) and the hypertension-associated genetic variants T174M and M235T in the angiotensinogen (AGT) gene were determined. Serum XT-I activities in male and female PXE patients were significantly increased compared to unaffected family members (male patients, mean value 0.96 mU/l, SD 0.37; male relatives, 0.78 mU/l, SD 0.29; female patients, 0.91 mU/l, SD 0.31; female relatives, 0.76 mU/l, SD 0.34; p<0.05). The mean XT-I activities in PXE patients with hypertension were 24% higher than in patients without increased blood pressure (p<0.05). The AGT T174M and M235T frequencies were not different in hypertensive PXE patients, normotensive PXE patients, family members or blood donors. Our data show that the altered proteoglycan biosynthesis in PXE patients is closely related to an increased XT-I activity in blood. Serum XT-I, the novel fibrosis marker, may be useful for the assessment of extracellular matrix alterations and disease activity in PXE.

Role of Serum Fetuin-A, a Major Inhibitor of Systemic Calcification, in Pseudoxanthoma Elasticum

“…We determined the occurrence of the c.3421CϾT mutation in PXE patients and their relatives as we have described previously (13,32 ). We found 11 (10%) homozygous and 40 (36.4%) heterozygous carriers of the common c.3421CϾT mutation in the patient group, whereas 13 (24.5%) relatives were heterozygous for this mutation.…”

“…Further investigations revealed enhanced elastin degradation leading to high amounts of demosines in the urine and plasma of PXE patients (31 ). We recently found increased xylosyltransferase I activity in the sera of PXE patients, which reflects the extracellular matrix alterations (32 ). Despite these findings, the implication of MRP6 in calcium-phosphate metabolism remains unknown.…”

Mutational analysis of theABCC6 gene and the proximalABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)

“…Using a limited haplotype analysis with the microsatellite markers D16B9621 and D16S764, the five intragenic SNPs c.1841T>C, c.2490C>T, c.3803G>A, c.4404-76A>G and c.4404-31G>A and the intragenic mutation c.3421C>T, a deletion of the whole ABCC6 gene could be excluded in homozygous state in all patients and in heterozygous state in all but 2 PXE patients. Saux et al, 2001;B, Miksch et al, 2005;C, Cai et al, 2001;D, Chassaing et al, 2004;E, Meloni et al, 2001;F, Hendig et al, 2004;G, Schulz et al, 2005a;H, Hu et al, 2003;I, Uitto et al, 2001;J, Le Saux et al, 2000;K, Gheduzzi et al, 2004;L, Schulz et al, 2005b;M, Götting et al, 2004;N, Ringpfeil et al, 2000;O, Bergen et al, 2000;P, Struk et al, 2000;Q, Pulkkinen et al, 2001;R, Ringpfeil et al, 2001;S, Götting et al, 2005. F = female, M = male, wt = wild-type, hm = homozygote, ht = heterozygote, cht = compound heterozygote, nd = not determined, MSM = microsatellite marker, E = eyes, S = skin, G = gastrointestinum, H = heart, V = vascular tissue and A = arterial hypertension. a The PXE families are consecutively numbered and the affected family members are indicated by following numbers.…”

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

“…12,13 Indeed, several studies reported alterations in systemic blood components in PXE patients and mouse models due to MRP6 deficiency. [14][15][16][17][18][19][20] Accordingly, PXE was assumed to be primarily a metabolic disorder. 12,[21][22][23] In contrast, results of several studies also point to a local role for ABCC6/MRP6 as expression of the protein was detected in dermal fibroblasts from healthy controls whereas it was found to be absent in fibroblasts from PXE patients.…”