共查询到20条相似文献,搜索用时 31 毫秒
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Klesert TR Cho DH Clark JI Maylie J Adelman J Snider L Yuen EC Soriano P Tapscott SJ 《Nature genetics》2000,25(1):105-109
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CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus 总被引:15,自引:0,他引:15
Filippova GN Thienes CP Penn BH Cho DH Hu YJ Moore JM Klesert TR Lobanenkov VV Tapscott SJ 《Nature genetics》2001,28(4):335-343
An expansion of a CTG repeat at the DM1 locus causes myotonic dystrophy (DM) by altering the expression of the two adjacent genes, DMPK and SIX5, and through a toxic effect of the repeat-containing RNA. Here we identify two CTCF-binding sites that flank the CTG repeat and form an insulator element between DMPK and SIX5. Methylation of these sites prevents binding of CTCF, indicating that the DM1 locus methylation in congenital DM would disrupt insulator function. Furthermore, CTCF-binding sites are associated with CTG/CAG repeats at several other loci. We suggest a general role for CTG/CAG repeats as components of insulator elements at multiple sites in the human genome. 相似文献
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The myotonic dystrophy (DM) mutation has recently been identified as an unstable trinucleotide CTG repeat which is present 5-30 times in the normal population but which is amplified up to 2,000 times in DM. We have determined the status of the CTG repeat in 272 DM individuals. Infants with severe congenital DM, as well as their mothers, are shown to have on average a greater amplification of the CTG repeat than is seen in the noncongenital DM population. This fact, when viewed in conjunction with the tendency to increased CTG repeat length in our DM kindreds, provides evidence for the existence of genetic anticipation in the transmission of DM. 相似文献
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N H Gehring U Frede G Neu-Yilik P Hundsdoerfer B Vetter M W Hentze A E Kulozik 《Nature genetics》2001,28(4):389-392
The G-->A mutation at position 20210 of the prothrombin or coagulation factor II gene (F2) represents a common genetic risk factor for the occurrence of thromboembolic events. This mutation affects the 3'-terminal nucleotide of the 3' untranslated region (UTR) of the mRNA and causes elevated prothrombin plasma concentrations by an unknown mechanism. Here, we show that the mutation does not affect the amount of pre-mRNA, the site of 3' end cleavage or the length of the poly(A) tail of the mature mRNA. Rather, we demonstrate that the physiological F2 3' end cleavage signal is inefficient and that F2 20210 G-->A represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3' end processing and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3' end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210 G-->A mutation in the pathogenesis of thrombophilia. This work also illustrates the pathophysiologic importance of quantitatively minor aberrations of RNA metabolism. 相似文献
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Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele 总被引:19,自引:0,他引:19
Morahan G Huang D Ymer SI Cancilla MR Stephen K Dabadghao P Werther G Tait BD Harrison LC Colman PG 《Nature genetics》2001,27(2):218-221
Type 1 diabetes (T1D; or insulin-dependent diabetes mellitus, IDDM) is an autoimmune disease with both genetic and environmental components. In addition to the human leukocyte antigen (HLA) complex, the single major genetic contributor of susceptibility, an unknown number of other unidentified genes are required to mediate disease. Although many loci conferring susceptibility to T1D have been mapped, their identification has proven problematic due to the complex nature of this disease. Our strategy for finding T1D susceptibility genes has been to test for human homologues of loci implicated in diabetes-prone NOD (non-obese diabetic) mice, together with application of biologically relevant stratification methods. We report here a new susceptibility locus, IDDM18, located near the interleukin-12 (IL-12)p40 gene, IL12B. Significant bias in transmission of IL12B alleles was observed in affected sibpairs and was confirmed in an independent cohort of simplex families. A single base change in the 3' UTR showed strong linkage disequilibrium with the T1D susceptibility locus. The IL12B 3' UTR alleles showed different levels of expression in cell lines. Variation in IL-12p40 production may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases. 相似文献
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Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. 总被引:13,自引:0,他引:13
R C Betz B G Schoser D Kasper K Ricker A Ramírez V Stein T Torbergsen Y A Lee M M N?then T F Wienker J P Malin P Propping A Reis W Mortier T J Jentsch M Vorgerd C Kubisch 《Nature genetics》2001,28(3):218-219
Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases. 相似文献
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A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep 总被引:38,自引:0,他引:38
Clop A Marcq F Takeda H Pirottin D Tordoir X Bibé B Bouix J Caiment F Elsen JM Eychenne F Larzul C Laville E Meish F Milenkovic D Tobin J Charlier C Georges M 《Nature genetics》2006,38(7):813-818
Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov x Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation. 相似文献
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Plzf regulates limb and axial skeletal patterning 总被引:20,自引:0,他引:20
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Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency 总被引:13,自引:0,他引:13
Irwin WA Bergamin N Sabatelli P Reggiani C Megighian A Merlini L Braghetta P Columbaro M Volpin D Bressan GM Bernardi P Bonaldo P 《Nature genetics》2003,35(4):367-371
Collagen VI is an extracellular matrix protein that forms a microfilamentous network in skeletal muscles and other organs. Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy. We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy. The pathophysiological defects and mechanisms leading to the myopathic disorder were not known. Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. We found a latent mitochondrial dysfunction in myofibers of Col6a1-/- mice on incubation with the selective F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ deregulation and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1-/- myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Treatment of Col6a1-/- mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicate that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention. 相似文献
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Chromatin packaging in mammalian spermatozoa requires an ordered replacement of the somatic histones by two classes of spermatid-specific basic proteins, the transition proteins and the protamines. Temporal expression of transition proteins and protamines during spermatid differentiation is under translational control, and premature translation of protamine 1 leads to precocious nuclear condensation and sterility. We have previously suggested that the double-stranded (ds) RNA binding protein Prbp (encoded by the gene Tarbp2) functions as a translational regulator during mouse spermatogenesis. Here we show that Prbp is required for proper translational activation of the mRNAs encoding the protamines. We generated mice that carry a targeted disruption of Tarbp2 and determined that they were sterile and severely oligospermic. Using immunohistological analysis, we determined that the endogenous Prm2 mRNA and a reporter mRNA carrying protamine 1 translational-control elements were translated in a mosaic pattern. We showed that failure to synthesize the protamines resulted in delayed replacement of the transition proteins and subsequent failure of spermiation. The timing of Prbp expression suggests that it may function as a chaperone in the assembly of specific translationally regulated ribonucleoprotein particles. 相似文献
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Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses 总被引:13,自引:0,他引:13
Mutations in the dystrophin gene (DMD) and in genes encoding several dystrophin-associated proteins result in Duchenne and other forms of muscular dystrophy. alpha-Dystroglycan (Dg) binds to laminins in the basement membrane surrounding each myofibre and docks with beta-Dg, a transmembrane protein, which in turn interacts with dystrophin or utrophin in the subplasmalemmal cytoskeleton. alpha- and beta-Dgs are thought to form the functional core of a larger complex of proteins extending from the basement membrane to the intracellular cytoskeleton, which serves as a superstructure necessary for sarcolemmal integrity. Dgs have also been implicated in the formation of synaptic densities of acetylcholine receptors (AChRs) on skeletal muscle. Here we report that chimaeric mice generated with ES cells targeted for both Dg alleles have skeletal muscles essentially devoid of Dgs and develop a progressive muscle pathology with changes emblematic of muscular dystrophies in humans. In addition, many neuromuscular junctions are disrupted in these mice. The ultrastructure of basement membranes and the deposition of laminin within them, however, appears unaffected in Dg-deficient muscles. We conclude that Dgs are necessary for myofibre survival and synapse differentiation or stability, but not for the formation of the muscle basement membrane, and that Dgs may have more than a purely structural function in maintaining muscle integrity. 相似文献
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Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice 总被引:23,自引:0,他引:23
LaVaute T Smith S Cooperman S Iwai K Land W Meyron-Holtz E Drake SK Miller G Abu-Asab M Tsokos M Switzer R Grinberg A Love P Tresser N Rouault TA 《Nature genetics》2001,27(2):209-214
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Canalization, also known as developmental robustness, describes an organism's ability to produce the same phenotype despite genotypic variations and environmental influences. In Drosophila, Hsp90, the trithorax-group proteins and transposon silencing have been previously implicated in canalization. Despite this, the molecular mechanism underlying canalization remains elusive. Here using a Drosophila eye-outgrowth assay sensitized by the dominant Kr(irregular facets-1)(Kr(If-1)) allele, we show that the Piwi-interacting RNA (piRNA) pathway, but not the short interfering RNA or micro RNA pathway, is involved in canalization. Furthermore, we isolated a protein complex composed of Hsp90, Piwi and Hop, the Hsp70/Hsp90 organizing protein homolog, and we demonstrated the function of this complex in canalization. Our data indicate that Hsp90 and Hop regulate the piRNA pathway through Piwi to mediate canalization. Moreover, they point to epigenetic silencing of the expression of existing genetic variants and the suppression of transposon-induced new genetic variation as two major mechanisms underlying piRNA pathway-mediated canalization. 相似文献