Serum fetuin-A was higher in female PXE patients with cardiovascular involvement than in the corresponding male group (P <0.05). The fetuin-A polymorphism frequencies did not differ among PXE patients, family members, and blood donors. Conclusion: A deficiency of multidrug resistance-associated protein 6 leads to alteration of circulating sub-
Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G>T. In the ABCC6 promoter we found the polymorphisms c.-127C>T, c.-132C>T, and c.-219A>C. The difference in the c.-219A>C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A>C is located in a transcriptional activator sequence of the ABCC6 promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE.
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.
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 (PXE; OMIM 177850 and 264800) is a rare heritable disorder of the connective tissue affecting the extracellular matrix of the skin, eyes, gastrointestinal system, and cardiovascular system. It has recently been found that mutations in the ABCC6 gene encoding the multidrug resistance-associated protein (MRP) 6 cause PXE. This study examined novel mutations in the ABCC6 gene in our cohort of 76 German PXE patients and 54 unaffected or not yet affected relatives with a view to expanding the known mutational spectrum of the gene. Mutational analysis was performed using denaturing high-performance liquid chromatography and direct sequencing. The mutational screening revealed a total of 22 different ABCC6 sequence variations. We identified seven novel and four previously described PXE-associated mutations as well as eight novel neutral ABCC6 sequence variants. The new PXE-associated mutations included five missense mutations, one single base pair deletion, and one larger out-of-frame deletion. We suspect that the novel missense mutations lead to an impaired function of MRP6. Both deletions are predicted to result in a dysfunctional MRP6 protein. The seven new ABCC6 mutations were not present in 200 alleles from healthy blood donors which served as a control cohort. Most of the PXE patients who were found to carry PXE-causing ABCC6 mutations were assumed to manifest the PXE phenotype because of a compound heterozygous genotype. However, a genotype-phenotype correlation could not be established for the detected ABCC6 mutations. In summary, our data give a further insight into the spectrum of ABCC6 mutations in PXE patients.
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