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Haploinsufficiency

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https://www.readbyqxmd.com/read/28319090/a-single-copy-sleeping-beauty-transposon-mutagenesis-screen-identifies-new-pten-cooperating-tumor-suppressor-genes
#1
Jorge de la Rosa, Julia Weber, Mathias Josef Friedrich, Yilong Li, Lena Rad, Hannes Ponstingl, Qi Liang, Sandra Bernaldo de Quirós, Imran Noorani, Emmanouil Metzakopian, Alexander Strong, Meng Amy Li, Aurora Astudillo, María Teresa Fernández-García, María Soledad Fernández-García, Gary J Hoffman, Rocío Fuente, George S Vassiliou, Roland Rad, Carlos López-Otín, Allan Bradley, Juan Cadiñanos
The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer...
March 20, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28319062/ctcf-genetic-alterations-in-endometrial-carcinoma-are-pro-tumorigenic
#2
A D Marshall, C G Bailey, K Champ, M Vellozzi, P O'Young, C Metierre, Y Feng, A Thoeng, A M Richards, U Schmitz, M Biro, R Jayasinghe, L Ding, L Anderson, E R Mardis, J E J Rasko
CTCF is a haploinsufficient tumour suppressor gene with diverse normal functions in genome structure and gene regulation. However the mechanism by which CTCF haploinsufficiency contributes to cancer development is not well understood. CTCF is frequently mutated in endometrial cancer. Here we show that most CTCF mutations effectively result in CTCF haploinsufficiency through nonsense-mediated decay of mutant transcripts, or loss-of-function missense mutation. Conversely, we identified a recurrent CTCF mutation K365T, which alters a DNA binding residue, and acts as a gain-of-function mutation enhancing cell survival...
March 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28316978/identification-of-significant-pathways-induced-by-pax5-haploinsufficiency-based-on-protein-protein-interaction-networks-and-cluster-analysis-in-raji-cell-line
#3
Jia Gu, TongJuan Li, Lei Zhao, Xue Liang, Xing Fu, Jue Wang, Zhen Shang, Wei Huang, Jianfeng Zhou
PAX5 encodes a transcription factor essential for B-cell differentiation, and PAX5 haploinsufficiency is involved in tumorigenesis. There were few studies on how PAX5 haploinsufficiency regulated genes expression to promote tumorigenesis. In this study, we constructed the cell model of PAX5 haploinsufficiency using gene editing technology in Raji cells, detected differentially expressed genes in PAX5 haploinsufficiency Raji cells, and used protein-protein interaction networks and cluster analysis to comprehensively investigate the cellular pathways involved in PAX5 haploinsufficiency...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28303854/clinical-auditory-phenotypes-associated-with-gata3-gene-mutations-in-familial-hypoparathyroidism-deafness-renal-dysplasia-syndrome
#4
Li Wang, Qiong-Fen Lin, Hong-Yang Wang, Jing Guan, Lan Lan, Lin-Yi Xie, Lan Yu, Ju Yang, Cui Zhao, Jin-Long Liang, Han-Lin Zhou, Huan-Ming Yang, Wen-Ping Xiong, Qiu-Jing Zhang, Da-Yong Wang, Qiu-Ju Wang
BACKGROUND: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases. METHODS: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations...
March 20, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28301459/blepharocheilodontic-syndrome-is-a-cdh1-pathway-related-disorder-due-to-mutations-in-cdh1-and-ctnnd1
#5
Jamal Ghoumid, Morgane Stichelbout, Anne-Sophie Jourdain, Frederic Frenois, Sophie Lejeune-Dumoulin, Marie-Pierre Alex-Cordier, Marine Lebrun, Pierre Guerreschi, Veronique Duquennoy-Martinot, Matthieu Vinchon, Joel Ferri, Matthieu Jung, Serge Vicaire, Clemence Vanlerberghe, Fabienne Escande, Florence Petit, Sylvie Manouvrier-Hanu
PURPOSE: Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown. METHODS: We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families. RESULTS: We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency...
March 16, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28286691/spina-bifida-pathogenesis-mechanisms-and-genes-in-mice-and-humans
#6
REVIEW
Siti W Mohd-Zin, Ahmed I Marwan, Mohamad K Abou Chaar, Azlina Ahmad-Annuar, Noraishah M Abdul-Aziz
Spina bifida is among the phenotypes of the larger condition known as neural tube defects (NTDs). It is the most common central nervous system malformation compatible with life and the second leading cause of birth defects after congenital heart defects. In this review paper, we define spina bifida and discuss the phenotypes seen in humans as described by both surgeons and embryologists in order to compare and ultimately contrast it to the leading animal model, the mouse. Our understanding of spina bifida is currently limited to the observations we make in mouse models, which reflect complete or targeted knockouts of genes, which perturb the whole gene(s) without taking into account the issue of haploinsufficiency, which is most prominent in the human spina bifida condition...
2017: Scientifica
https://www.readbyqxmd.com/read/28285794/missense-mutation-in-grn-gene-affecting-rna-splicing-and-plasma-progranulin-level-in-a-family-affected-by-frontotemporal-lobar-degeneration
#7
Simona Luzzi, Lara Colleoni, Paola Corbetta, Sara Baldinelli, Chiara Fiori, Francesca Girelli, Mauro Silvestrini, Paola Caroppo, Giorgio Giaccone, Fabrizio Tagliavini, Giacomina Rossi
Gene coding for progranulin, GRN, is a major gene linked to frontotemporal lobar degeneration. While most of pathogenic GRN mutations are null mutations leading to haploinsufficiency, GRN missense mutations do not have an obvious pathogenicity, and only a few have been revealed to act through different pathogenetic mechanisms, such as cytoplasmic missorting, protein degradation, and abnormal cleavage by elastase. The aim of this study was to disclose the pathogenetic mechanisms of the GRN A199V missense mutation, which was previously reported not to alter physiological progranulin features but was associated with a reduced plasma progranulin level...
February 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28283832/genetic-and-phenotypic-dissection-of-1q43q44-microdeletion-syndrome-and-neurodevelopmental-phenotypes-associated-with-mutations-in-zbtb18-and-hnrnpu
#8
Christel Depienne, Caroline Nava, Boris Keren, Solveig Heide, Agnès Rastetter, Sandrine Passemard, Sandra Chantot-Bastaraud, Marie-Laure Moutard, Pankaj B Agrawal, Grace VanNoy, Joan M Stoler, David J Amor, Thierry Billette de Villemeur, Diane Doummar, Caroline Alby, Valérie Cormier-Daire, Catherine Garel, Pauline Marzin, Sophie Scheidecker, Anne de Saint-Martin, Edouard Hirsch, Christian Korff, Armand Bottani, Laurence Faivre, Alain Verloes, Christine Orzechowski, Lydie Burglen, Bruno Leheup, Joelle Roume, Joris Andrieux, Frenny Sheth, Chaitanya Datar, Michael J Parker, Laurent Pasquier, Sylvie Odent, Sophie Naudion, Marie-Ange Delrue, Cédric Le Caignec, Marie Vincent, Bertrand Isidor, Florence Renaldo, Fiona Stewart, Annick Toutain, Udo Koehler, Birgit Häckl, Celina von Stülpnagel, Gerhard Kluger, Rikke S Møller, Deb Pal, Tord Jonson, Maria Soller, Nienke E Verbeek, Mieke M van Haelst, Carolien de Kovel, Bobby Koeleman, Glen Monroe, Gijs van Haaften, Tania Attié-Bitach, Lucile Boutaud, Delphine Héron, Cyril Mignot
Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes...
April 2017: Human Genetics
https://www.readbyqxmd.com/read/28283467/responsiveness-of-brca1-and-trp53-deficiency-induced-mammary-preneoplasia-to-selective-estrogen-modulators-versus-an-aromatase-inhibitor-in-mus-musculus
#9
Sahar J Alothman, Weisheng Wang, David S Goerlitz, Md Islam, Xiaogang Zhong, Archana Kishore, Redha I Azhar, Bhaskar V Kallakury, Priscilla A Furth
An intervention study initiated at age 4 months compared the impact of tamoxifen (25 mg), raloxifene (22.5 mg), and letrozole (2.5 mg) administered by 60-day release subcutaneous pellet on mammary preneoplasia prevalence at age 6 months in conditional genetically engineered mouse models with different Breast cancer 1 (Brca1) gene dosages targeted to mammary epithelial cells and germline Tumor protein P53 (Trp53) haploinsufficiency (10-16/cohort). The proportion of unexposed control mice demonstrating mammary preneoplasia at age 6 months was highest in Brca1(fl11/fl11/Cre/p53-/+) (54%) mice followed by Brca1(WT/fl11/Cre/p53-/+) mice (30%)...
March 10, 2017: Cancer Prevention Research
https://www.readbyqxmd.com/read/28281657/a-gcsfr-csf3r-zebrafish-mutant-models-the-persistent-basal-neutrophil-deficiency-of-severe-congenital-neutropenia
#10
Vahid Pazhakh, Sharon Clark, M Cristina Keightley, Graham J Lieschke
Granulocyte colony-stimulating factor (GCSF) and its receptor (GCSFR), also known as CSF3 and CSF3R, are required to maintain normal neutrophil numbers during basal and emergency granulopoiesis in humans, mice and zebrafish. Previous studies identified two zebrafish CSF3 ligands and a single CSF3 receptor. Transient antisense morpholino oligonucleotide knockdown of both these ligands and receptor reduces neutrophil numbers in zebrafish embryos, a technique widely used to evaluate neutrophil contributions to models of infection, inflammation and regeneration...
March 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28273074/a-rare-il33-loss-of-function-mutation-reduces-blood-eosinophil-counts-and-protects-from-asthma
#11
Dirk Smith, Hannes Helgason, Patrick Sulem, Unnur Steina Bjornsdottir, Ai Ching Lim, Gardar Sveinbjornsson, Haruki Hasegawa, Michael Brown, Randal R Ketchem, Monica Gavala, Logan Garrett, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Olafur T Magnusson, Gudmundur I Eyjolfsson, Isleifur Olafsson, Pall Torfi Onundarson, Olof Sigurdardottir, David Gislason, Thorarinn Gislason, Bjorn Runar Ludviksson, Dora Ludviksdottir, H Marike Boezen, Andrea Heinzmann, Marcus Krueger, Celeste Porsbjerg, Tarunveer S Ahluwalia, Johannes Waage, Vibeke Backer, Klaus A Deichmann, Gerard H Koppelman, Klaus Bønnelykke, Hans Bisgaard, Gisli Masson, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, James A Johnston, Ingileif Jonsdottir, Kari Stefansson
IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28271814/gata2-null-mutation-associated-with-incomplete-penetrance-in-a-family-with-emberger-syndrome
#12
Aniel Jessica Leticia Brambila-Tapia, José Elías García-Ortiz, Pascal Brouillard, Ha-Long Nguyen, Miikka Vikkula, Blanca Estela Ríos-González, Roberto de Jesús Sandoval-Muñiz, Ana Karen Sandoval-Talamantes, Lucina Bobadilla-Morales, Jorge Román Corona-Rivera, Lisette Arnaud-Lopez
INTRODUCTION: GATA2 mutations are associated with several conditions, including Emberger syndrome which is the association of primary lymphedema with hematological anomalies and an increased risk for myelodysplasia and leukemia. OBJECTIVE: To describe a family with Emberger syndrome with incomplete penetrance. METHODS: A DNA sequencing of GATA2 gene was performed in the parents and offspring (five individuals in total). RESULTS: The family consisted of 5 individuals with a GATA2 null mutation (c...
March 8, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28271030/high-fidelity-glucagon-creer-mouse-line-generated-by-crispr-cas9-assisted-gene-targeting
#13
Amanda M Ackermann, Jia Zhang, Aryel Heller, Anna Briker, Klaus H Kaestner
OBJECTIVE: α-cells are the second most prominent cell type in pancreatic islets and are responsible for producing glucagon to increase plasma glucose levels in times of fasting. α-cell dysfunction and inappropriate glucagon secretion occur in both type 1 and type 2 diabetes. Thus, there is growing interest in studying both normal function and pathophysiology of α-cells. However, tools to target gene ablation or activation specifically of α-cells have been limited, compared to those available for β-cells...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28270404/pbx1-haploinsufficiency-leads-to-syndromic-congenital-anomalies-of-the-kidney-and-urinary-tract-cakut-in-humans
#14
Pauline Le Tanno, Julie Breton, Marie Bidart, Véronique Satre, Radu Harbuz, Pierre F Ray, Caroline Bosson, Klaus Dieterich, Sylvie Jaillard, Sylvie Odent, Gemma Poke, Rachel Beddow, Maria Christina Digilio, Antonio Novelli, Laura Bernardini, Maria Antonietta Pisanti, Luisa Mackenroth, Karl Hackmann, Ida Vogel, Rikke Christensen, Siv Fokstuen, Frédérique Béna, Florence Amblard, Francoise Devillard, Gaelle Vieville, Alexia Apostolou, Pierre-Simon Jouk, Fitsum Guebre-Egziabher, Hervé Sartelet, Charles Coutton
BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion. METHODS: We describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA)...
March 7, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28264936/deletion-of-ribosomal-protein-genes-is-a-common-vulnerability-in-human-cancer-especially-in-concert-with-tp53-mutations
#15
Ram Ajore, David Raiser, Marie McConkey, Magnus Jöud, Bernd Boidol, Brenton Mar, Gordon Saksena, David M Weinstock, Scott Armstrong, Steven R Ellis, Benjamin L Ebert, Björn Nilsson
Heterozygous inactivating mutations in ribosomal protein genes (RPGs) are associated with hematopoietic and developmental abnormalities, activation of p53, and altered risk of cancer in humans and model organisms. Here we performed a large-scale analysis of cancer genome data to examine the frequency and selective pressure of RPG lesions across human cancers. We found that hemizygous RPG deletions are common, occurring in about 43% of 10,744 cancer specimens and cell lines. Consistent with p53-dependent negative selection, such lesions are underrepresented in TP53-intact tumors (P ≪ 10(-10)), and shRNA-mediated knockdown of RPGs activated p53 in TP53-wild-type cells...
March 6, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28263972/the-pre-rrna-processing-factor-def-is-rate-limiting-for-the-pathogenesis-of-mycn-driven-neuroblastoma
#16
T Tao, S B Sondalle, H Shi, S Zhu, A R Perez-Atayde, J Peng, S J Baserga, A T Look
The nucleolar factor, digestive organ expansion factor (DEF), has a key role in ribosome biogenesis, functioning in pre-ribosomal RNA (pre-rRNA) processing as a component of the small ribosomal subunit (SSU) processome. Here we show that the peripheral sympathetic nervous system (PSNS) is very underdeveloped in def-deficient zebrafish, and that def haploinsufficiency significantly decreases disease penetrance and tumor growth rate in a MYCN-driven transgenic zebrafish model of neuroblastoma that arises in the PSNS...
March 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28259234/primary-lymphedema-and-viral-warts-in-gata2-haploinsufficiency
#17
Juliana Perez Botero, Vilmarie Rodriguez
No abstract text is available yet for this article.
March 2017: Mayo Clinic Proceedings
https://www.readbyqxmd.com/read/28254817/deficient-circumferential-growth-is-the-primary-determinant-of-aortic-obstruction-attributable-to-partial-elastin-deficiency
#18
Yang Jiao, Guangxin Li, Arina Korneva, Alexander W Caulk, Lingfeng Qin, Matthew R Bersi, Qingle Li, Wei Li, Robert P Mecham, Jay D Humphrey, George Tellides
OBJECTIVE: Williams syndrome is characterized by obstructive aortopathy attributable to heterozygous loss of ELN, the gene encoding elastin. Lesions are thought to result primarily from excessive smooth muscle cell (SMC) proliferation and consequent medial expansion, although an initially smaller caliber and increased stiffness of the aorta may contribute to luminal narrowing. The relative contributions of such abnormalities to the obstructive phenotype had not been defined. APPROACH AND RESULTS: We quantified determinants of luminal stenosis in thoracic aortas of Eln(-/-) mice incompletely rescued by human ELN...
March 2, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28254758/role-of-mct1-and-caii-in-skeletal-muscle-ph-homeostasis-energetics-and-function-in-vivo-insights-from-mct1-haploinsufficient-mice
#19
Benjamin Chatel, David Bendahan, Christophe Hourdé, Luc Pellerin, Sylvain Lengacher, Pierre Magistretti, Yann Le Fur, Christophe Vilmen, Monique Bernard, Laurent A Messonnier
The purpose of this study was to investigate the effects of a partial suppression of monocarboxylate transporter (MCT)-1 on skeletal muscle pH, energetics, and function (MCT1(+/-) mice). Twenty-four MCT1(+/-) and 13 wild-type (WT) mice were subjected to a rest-exercise-recovery protocol, allowing assessment of muscle energetics (by magnetic resonance spectroscopy) and function. The study included analysis of enzyme activities and content of protein involved in pH regulation. Skeletal muscle of MCT1(+/-) mice had lower MCT1 (-61%; P < 0...
March 2, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28254467/the-influence-of-%C3%AE-actinin-3-deficiency-on-bone-remodelling-markers-in-young-men
#20
Itamar Levinger, Xu Yan, David Bishop, Peter J Houweling, Ioannis Papadimitriou, Fiona Munson, Elizabeth Byrnes, Daniele Vicari, Tara C Brennan-Speranza, Nir Eynon
There is a large individual variation in the bone remodelling markers (BRMs) osteocalcin (OC), procollagen 1 N-terminal propeptide (P1NP) and β-isomerized C-terminal telopeptide (β-CTx), as well as undercarboxylated osteocalcin (ucOC), at rest and in response to exercise. α-actinin-3 (ACTN3), a sarcomeric protein, is expressed in skeletal muscle and osteoblasts and may influence BRM levels and the cross-talk between muscle and bone. We tested the levels of serum BRMs in α-actinin-3 deficient humans (ACTN3 XX) at baseline, and following a single bout of exercise...
February 22, 2017: Bone
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