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  • Female  (3)
  • Nature Publishing Group (NPG)  (3)
  • American Chemical Society (ACS)
  • 2010-2014  (3)
  • 1
    Publication Date: 2013-05-15
    Description: Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706629/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706629/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zaidi, Samir -- Choi, Murim -- Wakimoto, Hiroko -- Ma, Lijiang -- Jiang, Jianming -- Overton, John D -- Romano-Adesman, Angela -- Bjornson, Robert D -- Breitbart, Roger E -- Brown, Kerry K -- Carriero, Nicholas J -- Cheung, Yee Him -- Deanfield, John -- DePalma, Steve -- Fakhro, Khalid A -- Glessner, Joseph -- Hakonarson, Hakon -- Italia, Michael J -- Kaltman, Jonathan R -- Kaski, Juan -- Kim, Richard -- Kline, Jennie K -- Lee, Teresa -- Leipzig, Jeremy -- Lopez, Alexander -- Mane, Shrikant M -- Mitchell, Laura E -- Newburger, Jane W -- Parfenov, Michael -- Pe'er, Itsik -- Porter, George -- Roberts, Amy E -- Sachidanandam, Ravi -- Sanders, Stephan J -- Seiden, Howard S -- State, Mathew W -- Subramanian, Sailakshmi -- Tikhonova, Irina R -- Wang, Wei -- Warburton, Dorothy -- White, Peter S -- Williams, Ismee A -- Zhao, Hongyu -- Seidman, Jonathan G -- Brueckner, Martina -- Chung, Wendy K -- Gelb, Bruce D -- Goldmuntz, Elizabeth -- Seidman, Christine E -- Lifton, Richard P -- 5U54HG006504/HG/NHGRI NIH HHS/ -- F30 HL123238/HL/NHLBI NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- U01 HG006546/HG/NHGRI NIH HHS/ -- U01 HL098123/HL/NHLBI NIH HHS/ -- U01 HL098147/HL/NHLBI NIH HHS/ -- U01 HL098153/HL/NHLBI NIH HHS/ -- U01 HL098162/HL/NHLBI NIH HHS/ -- U01 HL098163/HL/NHLBI NIH HHS/ -- U01-HL098123/HL/NHLBI NIH HHS/ -- U01-HL098147/HL/NHLBI NIH HHS/ -- U01-HL098153/HL/NHLBI NIH HHS/ -- U01-HL098162/HL/NHLBI NIH HHS/ -- U01-HL098163/HL/NHLBI NIH HHS/ -- U01-HL098188/HL/NHLBI NIH HHS/ -- U54 HG006504/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 13;498(7453):220-3. doi: 10.1038/nature12141. Epub 2013 May 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23665959" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Case-Control Studies ; Child ; Chromatin/chemistry/metabolism ; DNA Mutational Analysis ; Enhancer Elements, Genetic/genetics ; Exome/genetics ; Female ; Genes, Developmental/genetics ; Heart Diseases/*congenital/*genetics/metabolism ; Histones/chemistry/*metabolism ; Humans ; Lysine/chemistry/metabolism ; Male ; Methylation ; Mutation ; Odds Ratio ; Promoter Regions, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-01-24
    Description: Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278668/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boyden, Lynn M -- Choi, Murim -- Choate, Keith A -- Nelson-Williams, Carol J -- Farhi, Anita -- Toka, Hakan R -- Tikhonova, Irina R -- Bjornson, Robert -- Mane, Shrikant M -- Colussi, Giacomo -- Lebel, Marcel -- Gordon, Richard D -- Semmekrot, Ben A -- Poujol, Alain -- Valimaki, Matti J -- De Ferrari, Maria E -- Sanjad, Sami A -- Gutkin, Michael -- Karet, Fiona E -- Tucci, Joseph R -- Stockigt, Jim R -- Keppler-Noreuil, Kim M -- Porter, Craig C -- Anand, Sudhir K -- Whiteford, Margo L -- Davis, Ira D -- Dewar, Stephanie B -- Bettinelli, Alberto -- Fadrowski, Jeffrey J -- Belsha, Craig W -- Hunley, Tracy E -- Nelson, Raoul D -- Trachtman, Howard -- Cole, Trevor R P -- Pinsk, Maury -- Bockenhauer, Detlef -- Shenoy, Mohan -- Vaidyanathan, Priya -- Foreman, John W -- Rasoulpour, Majid -- Thameem, Farook -- Al-Shahrouri, Hania Z -- Radhakrishnan, Jai -- Gharavi, Ali G -- Goilav, Beatrice -- Lifton, Richard P -- KL2 RR024138/RR/NCRR NIH HHS/ -- KL2 RR024138-07/RR/NCRR NIH HHS/ -- P30 DK079310/DK/NIDDK NIH HHS/ -- P30 DK079310-04S1/DK/NIDDK NIH HHS/ -- P30-DK079310/DK/NIDDK NIH HHS/ -- UL1-RR024139/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 22;482(7383):98-102. doi: 10.1038/nature10814.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22266938" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Base Sequence ; Blood Pressure/genetics ; Carrier Proteins/chemistry/*genetics ; Cohort Studies ; Cullin Proteins/chemistry/*genetics ; Electrolytes ; Exons/genetics ; Female ; Gene Expression Profiling ; Genes, Dominant/genetics ; Genes, Recessive/genetics ; Genotype ; Homeostasis/genetics ; Humans ; Hydrogen-Ion Concentration ; Hypertension/complications/*genetics/physiopathology ; Male ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutation/*genetics ; Phenotype ; Potassium/metabolism ; Pseudohypoaldosteronism/complications/*genetics/physiopathology ; Sodium Chloride/metabolism ; Water-Electrolyte Imbalance/complications/*genetics/physiopathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-05-12
    Description: R-spondin proteins strongly potentiate Wnt signalling and function as stem-cell growth factors. Despite the biological and therapeutic significance, the molecular mechanism of R-spondin action remains unclear. Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. Inhibition of ZNRF3 enhances Wnt/beta-catenin signalling and disrupts Wnt/planar cell polarity signalling in vivo. Notably, R-spondin mimics ZNRF3 inhibition by increasing the membrane level of Wnt receptors. Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. Our study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hao, Huai-Xiang -- Xie, Yang -- Zhang, Yue -- Charlat, Olga -- Oster, Emma -- Avello, Monika -- Lei, Hong -- Mickanin, Craig -- Liu, Dong -- Ruffner, Heinz -- Mao, Xiaohong -- Ma, Qicheng -- Zamponi, Raffaella -- Bouwmeester, Tewis -- Finan, Peter M -- Kirschner, Marc W -- Porter, Jeffery A -- Serluca, Fabrizio C -- Cong, Feng -- England -- Nature. 2012 Apr 29;485(7397):195-200. doi: 10.1038/nature11019.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22575959" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Polarity/physiology ; Colorectal Neoplasms/genetics ; DNA-Binding Proteins/deficiency/genetics/metabolism ; Feedback, Physiological ; Female ; Frizzled Receptors/metabolism ; HEK293 Cells ; Humans ; Low Density Lipoprotein Receptor-Related Protein-6/metabolism ; Male ; Mice ; Mice, Knockout ; Oncogene Proteins/deficiency/genetics/metabolism ; Protein Stability ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/deficiency/genetics/metabolism ; Receptors, Wnt/*metabolism ; Thrombospondins/*metabolism ; Ubiquitin-Protein Ligases/chemistry/*deficiency/genetics/*metabolism ; Ubiquitination ; Wnt Signaling Pathway ; Xenopus ; Zebrafish ; beta Catenin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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