Hypoxia controls expression of kidney-pathogenicMUC1variants
Stephanie NaasRené KrügerKarl X. KnaupJulia NaasSteffen GramppMario SchifferMichael S. WiesenerJohannes Schödel
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The interplay between genetic and environmental factors influences the course of chronic kidney disease (CKD). In this context, genetic alterations in the kidney disease gene MUC1 (Mucin1) predispose to the development of CKD. These variations comprise the polymorphism rs4072037, which alters splicing of MUC1 mRNA, the length of a region with variable number of tandem repeats (VNTR), and rare autosomal-dominant inherited dominant-negative mutations in or 5' to the VNTR that causes autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1). As hypoxia plays a pivotal role in states of acute and chronic kidney injury, we explored the effects of hypoxia-inducible transcription factors (HIF) on the expression of MUC1 and its pathogenic variants in isolated primary human renal tubular cells. We defined a HIF-binding DNA regulatory element in the promoter-proximal region of MUC1 from which hypoxia or treatment with HIF stabilizers, which were recently approved for an anti-anemic therapy in CKD patients, increased levels of wild-type MUC1 and the disease-associated variants. Thus, application of these compounds might exert unfavorable effects in patients carrying MUC1 risk variants.Keywords:
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Variable-number tandem repeats (VNTRs) may evolve so rapidly that multiple profiles emerge during an outbreak. A total of 190 isolates from eight Salmonella enterica serovar Typhimurium outbreaks and 15 isolates from seven patients were analyzed by pulsed-field gel electrophoresis and VNTR typing. Small changes in loci were noted; otherwise, the VNTR profiles were stable during the course of the outbreaks.
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Direct repeat
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genomic DNA
Minisatellite
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Abstract The standard slipped-strand mispairing (SSM) model for the formation of variable number tandem repeats (VNTRs) proposes that a few tandem repeats, produced by chance mutations, provide the “raw material” for VNTR expansion. However, this model is unlikely to explain the formation of VNTRs with long motifs (e.g., minisatellites), because the likelihood of a tandem repeat forming by chance decreases rapidly as the length of the repeat motif increases. Phylogenetic reconstruction of the birth of a mitochondrial (mt) DNA minisatellite in guppies suggests that VNTRs with long motifs can form as a consequence of SSM at noncontiguous repeats. VNTRs formed in this manner have motifs longer than the noncontiguous repeat originally formed by chance and are flanked by one unit of the original, noncontiguous repeat. SSM at noncontiguous repeats can therefore explain the birth of VNTRs with long motifs and the “imperfect” or “short direct” repeats frequently observed adjacent to both mtDNA and nuclear VNTRs.
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Little is known about DNA tandem repeats across prokaryotes. We have recently described an enigmatic group of tandem repeats in bacterial genomes with a constant repeat size but variable sequence. These findings strongly suggest that tandem repeat size in some bacteria is under strong selective constraints. Here, we extend these studies and describe tandem repeats in a large set of Bacillus. Some species have very few repeats, while other species have a large number. Most tandem repeats have repeats with a constant size (either 52 or 20–21 nt), but a variable sequence. We characterize in detail these intriguing tandem repeats. Individual species have several families of tandem repeats with the same repeat length and different sequence. This result is in strong contrast with eukaryotes, where tandem repeats of many sizes are found in any species. We discuss the possibility that they are transcribed as small RNA molecules. They may also be involved in the stabilization of the nucleoid through interaction with proteins. We also show that the distribution of tandem repeats in different species has a taxonomic significance. The data we present for all tandem repeats and their families in these bacterial species will be useful for further genomic studies.
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Abstract MUC1 mucin is a large transmembrane glycoprotein whose extracelluler domain is composed of repeating units of a 20 amino acid sequence. In the cancer associated state, this protein expression becomes upregulated and underglycosylated. Previous studies, which show an enhanced binding of a 5‐repeat over a 1‐repeat MUC1 peptide to a panel of anti‐MUC1 antibodies, have led us to investigate the structural and dynamic consequences of increasing repeat number. Two MUC1 peptides were studied: a 16mer corresponding to slightly less than one full repeat of the MUC1 tandem repeat sequence (GVTSAPDTRPAPGSTA) and a 40mer corresponding to two full repeats of the MUC1 sequence (VTSAPDTRPAPGSTAPPAHG) 2 . Isotopically labeled versions of these MUC1 peptides were cloned, expressed, purified, and evaluated structurally and dynamically using 15 N‐ and 13 C‐edited NMR approaches. The data show that MUC1 structure, dynamics, and antibody binding affinity are invariant with increasing repeat number. In light of these results, we conclude that the enhanced antibody affinity of the 5‐repeat over the 1‐repeat MUC1 peptide is due to multivalency effects, and not due to the development of higher order structure in the longer length peptides. The implications of these results are discussed within the context of a multiple repeat MUC1 breast cancer vaccine design. © 2005 Wiley Periodicals, Inc. Biopolymers, 2005
MUC1
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Gao, J., Jiang, Z.-R., Liu, X., Zhao, Y.-H., Huang, L., Peng, H.-J., Zedan, D., Jin, S.-Y. and Zheng, Y.-C. 2014. Comparison of MUC1 variable number tandem repeat polymorphisms in three yak breeds/populations. Can. J. Anim. Sci. 94: 411-416. The objective of this study was to compare the MUC1 variable number tandem repeat polymorphisms with adjacent distribution regions in three yak (Bos grunniens) breeds/populations. A total of 215 yaks of three yak breeds/populations (Maiwa yak breed, Jiulong yak breed and Changtai yak population) were surveyed by the polymorphisms of Mucin 1 gene (MUC1). Six MUC1 alleles (B, C, D, F, G and H) forming 16 genotypes were identified. Cloning and sequencing of these alleles demonstrated that they differed in the numbers of variable number tandem repeats (VNTR) units ranging from 14 to 20, and allele H (14 VNTR units) was a new allele in yaks and observed only in Maiwa yak with a very low frequency. Cluster analysis based on MUC1 polymorphisms suggested that Changtai yak pop...
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MUC1
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Objective To study whether the variable number of tandem repeats polymorphism has been present in the aggrecan gene and its distribution in 133 Han Chinese in southern China. Methods The distribution of the polymorphisms of the aggrecan gene was detected by using polymerase chain reaction (PCR) in 77 male and 56 female Han Chinese aged 18 to 90 yreas. Results Eight tandem repeats of the aggrecan gene in different length were detectable in these 133 subjects. The moderate-length tandem repeats were more common, allele 27 accounting for 48.49%, allele 28 27.44%, and allele 26 12.03%; while the short or long tandem repeats were less, allele13 being 0.4%, allele 22 4.14%, allele 25 4.89%, allele 29 1.13%, and allele 32 1.88%. Conclusion The variable number of tandem repeats polymorphism is present in the aggrecan gene in Han Chinese in southern China. The moderate-length tandem repeats are present more frequently while less short or long tandem repeats occur.
Aggrecan
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