Impact of polymorphisms in the genes encoding xylosyltransferase I and a homologue in type 1 diabetic patients with and without nephropathy

Schön, Sylvia; Prante, Christian; Müller, Sandra; Schöttler, Manuela; Tarnow, Lise; Kühn, Joachim; Kleesiek, Knut; Götting, Christian

doi:10.1111/j.1523-1755.2005.00561.x

Cited by 15 publications

(16 citation statements)

References 31 publications

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“…XT-I is the initial and apparently rate-limiting enzyme in the biosynthesis of heparan sulfate proteoglycans. Therefore, we investigated in a large cohort of type 1 diabetic patients with and without diabetic nephropathy the distribution of four previously described variations in the XYLT-I and XYLT-II genes (16). These variations included a combination of a nucleotide exchange and an insertion in intron 5 of XYLT-II (IVS6 -9TϾC and IVS6 -14_IVS6 -13insG) and three SNPs.…”

Section: Genotype-phenotype Associationsmentioning

confidence: 99%

“…They could function as enhancers, silencers, or transcription factor binding sites and affect gene transcription or RNA splicing. However, we can exclude the linkage with exonic alterations because we screened all XYLT-I exons and the exon/intron junctions (16).…”

Section: Xylt-i)mentioning

confidence: 99%

“…Therefore, we have now investigated variations in the XYLT genes to analyze the hitherto unknown impact of the xylosyltransferases, the initial and committing step enzymes in proteoglycan homeostasis, in diabetic nephropathy. This follow-up study was carried out to elucidate the importance of four recently described XYLT variations conferring genetic susceptibility to microvascular complications in type 1 diabetic patients (16).…”

mentioning

confidence: 99%

“…Of these, Ͼ70% was accepted and a corresponding control group of patients with type 1 diabetes and persistent normal urinary albumin excretion rates was recruited from the outpatient clinic (17). The previously described 96 patients (16) were not considered in this study. The clinical characteristics of the investigated patients are summarized in Table 1.…”

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confidence: 99%

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The Xylosyltransferase I Gene Polymorphism c.343G>T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes

et al. 2006

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OBJECTIVE—Xylosyltransferase I (XT-I) is the chain-initiating enzyme in the biosynthesis of proteoglycans in basement membranes. It catalyzes the transfer of xylose to selected serine residues in the core protein. The XYLT-II gene codes for a protein highly homologous to XT-I. Proteoglycans are important components of basement membranes and are responsible for their permeability properties. Type 1 diabetic patients have an altered proteoglycan metabolism, which results in microvascular complications. Thus, genetic variations in the xylosyltransferase genes might be implicated in the initiation and progression of these complications. RESEARCH DESIGN AND METHODS—Genotyping of four genetic variations in the genes XYLT-I and XYLT-II was performed in 912 type 1 diabetic patients (453 with and 459 without diabetic nephropathy) using restriction fragment–length polymorphism. RESULTS—The distribution of the c.343G>T polymorphism in XYLT-I is significantly different between patients with and without diabetic nephropathy (P = 0.03). T-alleles were more frequent in patients with diabetic nephropathy (odds ratio 2.47 [95% CI 1.04–5.83]). The allelic frequencies of the other investigated XYLT-I and XYLT-II variations (XYLT-I: c.1989T>C in exon 9; XYLT-II: IVS6–9T>C and IVS6–14_IVS6–13insG in intron 5; and c.2402C>G: p.T801R in exon 11) were not different between patients with and without diabetic nephropathy. CONCLUSIONS—The XYLT-I c.343G>T polymorphism contributes to the genetic susceptibility to development of diabetic nephropathy in type 1 diabetic patients.

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Section: Genotype-phenotype Associationsmentioning

confidence: 99%

Section: Xylt-i)mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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The Xylosyltransferase I Gene Polymorphism c.343G>T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes

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“…Section 1734 solely to indicate this fact. biological importance since mutations in the XT-II gene are genetic risk factors for diseases that are characterized by an altered proteoglycan metabolism, such as pseudoxanthoma elasticum (14), osteoarthritis (15), or diabetic nephropathy (16).…”

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confidence: 99%

Human Xylosyltransferase II Is Involved in the Biosynthesis of the Uniform Tetrasaccharide Linkage Region in Chondroitin Sulfate and Heparan Sulfate Proteoglycans

Pönighaus

Ambrosius

Casanova

et al. 2007

Journal of Biological Chemistry

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Human xylosyltransferase I (XT-I) initiates the biosynthesis of the glycosaminoglycan (GAG) linkage tetrasaccharide in proteoglycans. Xylosyltransferase II (XT-II) is a protein homologous to XT-I but with hitherto unknown activity or physiological function. Here, we report the enzymatic activity of XT-II and provide evidence that XT-II initiates the biosynthesis of both heparan sulfate and chondroitin sulfate GAGs. Transfection of the xylosyltransferase-deficient Chinese hamster ovary mutant pgsA-745 with XT-I or XT-II coding cDNA completely restored GAG biosynthesis. GAG disaccharide analysis revealed that XT-I-and XT-II-transfected pgsA-745 cells produced similar amounts of chondroitin sulfate and heparan sulfate. Furthermore, a high xylosyltransferase activity was measured after transfection with cDNAs encoding either isozyme. Analysis of the enzyme activity revealed that XT-II catalyzes the transfer of xylose to similar peptide acceptors as XT-I but with different efficiency. The optimal XT-II acceptor was observed using a bikunin-related peptide (K m 5.2 M). Analysis of XT-I and XT-II mRNA expression in murine tissues showed a differential expression pattern for both enzymes. In particular, XT-II is highly expressed in liver tissue, where XT-I transcripts were not detected. This is the first report on the enzyme activity of XT-II and its involvement in chondroitin sulfate and heparan sulfate biosynthesis.

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Human xylosyltransferases in health and disease

Götting

Kühn

Kleesiek

2007

Cell. Mol. Life Sci.

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The xylosyltransferases I and II (XT-I, XT-II, EC 2.4.2.26) catalyze the transfer of xylose from UDP-xylose to selected serine residues in the proteoglycan core protein, which is the initial and ratelimiting step in glycosaminoglycan biosynthesis. Both xylosyltransferases are Golgi-resident enzymes and transfer xylose to similar core proteins acceptors. XT-I and XT-II are differentially expressed in cell types and tissues, although the reason for the existence of two xylosyltransferase isoforms in all higher organisms remains elusive. Serum xylosyltransferase activity was found to be a biochemical marker for the assessment of disease activity in systemic sclerosis and for the diagnosis of fibrotic remodeling processes. Furthermore, sequence variations in the XT-I and XT-II coding genes were identified as risk factors for diabetic nephropathy, osteoarthritis or pseudoxanthoma elasticum. These findings point to the important role of the xylosyltransferases as disease modifiers in pathologies which are characterized by an altered proteoglycan metabolism. The present review discusses recent advances in mammalian xylosyltransferases and the impact of xylosyltransferases in proteoglycan-associated diseases.

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Impact of polymorphisms in the genes encoding xylosyltransferase I and a homologue in type 1 diabetic patients with and without nephropathy

Abstract: We detected in our cohort associations between DNA sequence variations of genes encoding xylosyltransferases and the occurrence of altered clinical characteristics.

Cited by 15 publications

References 31 publications

The Xylosyltransferase I Gene Polymorphism c.343G>T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes

The Xylosyltransferase I Gene Polymorphism c.343G>T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes

Human Xylosyltransferase II Is Involved in the Biosynthesis of the Uniform Tetrasaccharide Linkage Region in Chondroitin Sulfate and Heparan Sulfate Proteoglycans

Human xylosyltransferases in health and disease

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Impact of polymorphisms in the genes encoding xylosyltransferase I and a homologue in type 1 diabetic patients with and without nephropathy

Abstract: We detected in our cohort associations between DNA sequence variations of genes encoding xylosyltransferases and the occurrence of altered clinical characteristics.

Cited by 15 publications

References 31 publications

The Xylosyltransferase I Gene Polymorphism c.343G&gt;T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes

The Xylosyltransferase I Gene Polymorphism c.343G&gt;T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes

Human Xylosyltransferase II Is Involved in the Biosynthesis of the Uniform Tetrasaccharide Linkage Region in Chondroitin Sulfate and Heparan Sulfate Proteoglycans

Human xylosyltransferases in health and disease

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The Xylosyltransferase I Gene Polymorphism c.343G>T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes

The Xylosyltransferase I Gene Polymorphism c.343G>T (p.A125S) Is a Risk Factor for Diabetic Nephropathy in Type 1 Diabetes