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

Schön, Sylvia; Prante, Christian; Bahr, Claudia; Tarnow, Lise; Kühn, Joachim; Kleesiek, Knut; Götting, Christian

doi:10.2337/dc06-0344

Cited by 10 publications

(4 citation statements)

References 28 publications

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“…Sequence analysis of the genomic DNA of 100 healthy blood donors revealed the occurrence of a microsatellite as well as two SNV in the XYLT1 promoter region, and points to a strong conservation. This hypothesis is confirmed by the description of only a few SNV, representing risk factors for proteoglycan-associated pathologies like diabetic nephropathy, and two extremely rare, naturally occurring defects in the XYLT1 gene so far [ 24 , 35 , 36 ]. The homozygous missense mutation c.1441C>T (p.R481W) was elucidated to evoke functional enzymatic alterations causing intellectual disability and dwarfism [ 12 ].…”

Section: Discussionmentioning

confidence: 80%

First description of the complete human xylosyltransferase-I promoter region

et al. 2014

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BackgroundHuman xylosyltransferase-I (XT-I) catalyzes the rate-limiting step in proteoglycan glycosylation. An increase in XYLT1 mRNA expression and serum XT activity is associated with diseases characterized by abnormal extracellular matrix accumulation like, for instance, fibrosis. Nevertheless, physiological and pathological mechanisms of transcriptional XT regulation remain elusive.ResultsTo elucidate whether promoter variations might affect the naturally occurring variability in serum XT activity, a complete sequence analysis of the XYLT1 promoter was performed in genomic DNA of healthy blood donors. Based on promoter amplification by a specialized PCR technique, sequence analysis revealed a fragment of 238 bp, termed XYLT1238*, which has never been described in the human XYLT1 reference sequence so far. In silico characterization of this unconsidered fragment depicted an evolutionary conservation between sequences of Homo sapiens and Pan troglodytes (chimpanzee) or Mus musculus (mouse), respectively. Promoter activity studies indicated that XYLT1238* harbors various transcription factor binding sites affecting basal XYLT1 expression and inducibility by transforming growth factor-β1, the key fibrotic mediator.A microsatellite and two single nucleotide variants (SNV), c.-403C>T and c.-1088C>A, were identified and genotyped in 100 healthy blood donors. Construct associated changes in XYLT1 promoter activity were detected for several sequence variants, whereas serum XT activity was only marginally affected.ConclusionsOur findings describe for the first time the entire XYLT1 promoter sequence and provide new insights into transcriptional regulation of XT-I. Future studies should analyze the impact of regulatory XYLT1 promoter variations on XT-associated diseases.

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Section: Discussionmentioning

confidence: 80%

First description of the complete human xylosyltransferase-I promoter region

et al. 2014

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“…Xylosyltransferase activity has also been used as a biomarker for several other diseases including diabetic nephropathy, male infertility and osteoarthritis (Gotting et al, 2002; Götting et al, 2007; Götting et al, 1999; Schön et al, 2006b). Most recently, Schreml et al, identified a homozygous point mutation in XYLT1 (c.C1441T) in two siblings exhibiting short stature and other skeletal anomalies and developmental defects (Schreml et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Forward genetics defines Xylt1 as a key, conserved regulator of early chondrocyte maturation and skeletal length

Mis

Liem

Kong

et al. 2014

Developmental Biology

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The long bones of the vertebrate body are built by the initial formation of a cartilage template that is later replaced by mineralized bone. The proliferation and maturation of the skeletal precursor cells (chondrocytes) within the cartilage template and their replacement by bone is a highly coordinated process which, if misregulated, can lead to a number of defects including dwarfism and other skeletal deformities. This is exemplified by the fact that abnormal bone development is one of the most common types of human birth defects. Yet, many of the factors that initiate and regulate chondrocyte maturation are not known. We identified a recessive dwarf mouse mutant (pug) from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. pug mutant skeletal elements are patterned normally during development, but display a ~20% length reduction compared to wild-type embryos. We show that the pug mutation does not lead to changes in chondrocyte proliferation but instead promotes premature maturation and early ossification, which ultimately leads to disproportionate dwarfism. Using sequence capture and high-throughput sequencing, we identified a missense mutation in the Xylosyltransferase 1 (Xylt1) gene in pug mutants. Xylosyltransferases catalyze the initial step in glycosaminoglycan (GAG) chain addition to proteoglycan core proteins, and these modifications are essential for normal proteoglycan function. We show that the pug mutation disrupts Xylt1 activity and subcellular localization, leading to a reduction in GAG chains in pug mutants. The pug mutant serves as a novel model for mammalian dwarfism and identifies a key role for proteoglycan modification in the initiation of chondrocyte maturation.

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“…The pathogenesis of diabetic nephropathy is multi-factorial, and multiple genetic risk factors are discussed [167]. Scanning of xylosyl-1510 C. Gçtting, J. Kuhn and K. Kleesiek Proteoglycan xylosyltransferases transferase genes in type 1 diabetic patients showed that the xylt-1 variation p.A115S confers a 2.5-fold increased risk for diabetic nephropathy [30,163]. This is the first evidence that mutations in the enzymes involved in proteoglycan assembly can serve as risk factors for diabetic nephropathy.…”

Section: Sequence Variations In the Xylosyltransferase Genesmentioning

confidence: 99%

“…These results and the absence of nonsense mutations, frame-shift alterations and splice-site mutations point to the important role of the xylosyltransferases for human life. However, some sequence variations in xylosyltransferase genes that serve as major risk factors for proteoglycan-associated diseases could be identified ( Table 2, Table 3) [31,32,163]. Proteoglycans are important components of the glomerular basement membrane and are responsible for the size-and charge-dependent permeability of the basement membrane [1,165].…”

Section: Sequence Variations In the Xylosyltransferase Genesmentioning

confidence: 99%

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

Cited by 10 publications

References 28 publications

First description of the complete human xylosyltransferase-I promoter region

First description of the complete human xylosyltransferase-I promoter region

Forward genetics defines Xylt1 as a key, conserved regulator of early chondrocyte maturation and skeletal length

Human xylosyltransferases in health and disease

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