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Allelic exclusion

Suzanne Drury, Sarah Mason, Fiona McKay, Kitty Lo, Christopher Boustred, Lucy Jenkins, Lyn S Chitty
Our UK National Health Service regional genetics laboratory offers NIPD for autosomal dominant and de novo conditions (achondroplasia, thanataphoric dysplasia, Apert syndrome), paternal mutation exclusion for cystic fibrosis and a range of bespoke tests. NIPD avoids the risks associated with invasive testing, making prenatal diagnosis more accessible to families at high genetic risk. However, the challenge remains in offering definitive diagnosis for autosomal recessive diseases, which is complicated by the predominance of the maternal mutant allele in the cell-free DNA sample and thus requires a variety of different approaches...
2016: Advances in Experimental Medicine and Biology
Jonathan J Lyons, Xiaomin Yu, Jason D Hughes, Quang T Le, Ali Jamil, Yun Bai, Nancy Ho, Ming Zhao, Yihui Liu, Michael P O'Connell, Neil N Trivedi, Celeste Nelson, Thomas DiMaggio, Nina Jones, Helen Matthews, Katie L Lewis, Andrew J Oler, Ryan J Carlson, Peter D Arkwright, Celine Hong, Sherene Agama, Todd M Wilson, Sofie Tucker, Yu Zhang, Joshua J McElwee, Maryland Pao, Sarah C Glover, Marc E Rothenberg, Robert J Hohman, Kelly D Stone, George H Caughey, Theo Heller, Dean D Metcalfe, Leslie G Biesecker, Lawrence B Schwartz, Joshua D Milner
Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints...
October 17, 2016: Nature Genetics
María Abáigar, Cristina Robledo, Rocío Benito, Fernando Ramos, María Díez-Campelo, Lourdes Hermosín, Javier Sánchez-Del-Real, Jose M Alonso, Rebeca Cuello, Marta Megido, Juan N Rodríguez, Guillermo Martín-Núñez, Carlos Aguilar, Manuel Vargas, Ana A Martín, Juan L García, Alexander Kohlmann, M Consuelo Del Cañizo, Jesús M Hernández-Rivas
To explore novel genetic abnormalities occurring in myelodysplastic syndromes (MDS) through an integrative study combining array-based comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) in a series of MDS and MDS/myeloproliferative neoplasms (MPN) patients. 301 patients diagnosed with MDS (n = 240) or MDS/MPN (n = 61) were studied at the time of diagnosis. A genome-wide analysis of DNA copy number abnormalities was performed. In addition, a mutational analysis of DNMT3A, TET2, RUNX1, TP53 and BCOR genes was performed by NGS in selected cases...
2016: PloS One
Florian Geisler, Harald Gerhardus, Katrin Carberry, Wayne Davis, Erik Jorgensen, Christine Richardson, Olaf Bossinger, Rudolf E Leube
Intermediate filaments are major cytoskeletal components whose assembly into complex networks and isotype-specific functions are still largely unknown. Caenorhabditis elegans provides an excellent model system to study intermediate filament organization and function in vivo Its intestinal intermediate filaments localize exclusively to the endotube, a circumferential sheet just below the actin-based terminal web. A genetic screen for defects in the organization of intermediate filaments identified a mutation in the catalytic domain of the MAP kinase 7 ortholog sma-5(kc1) In sma-5(kc1) mutants pockets of lumen penetrate the cytoplasm of the intestinal cells...
October 12, 2016: Molecular Biology of the Cell
Mirco Dindo, Riccardo Montioli, Mirko Busato, Alejandro Giorgetti, Barbara Cellini, Carla Borri Voltattorni
In this work the dimerization process of the minor allelic form of human alanine glyoxylate aminotransferase, a pyridoxal 5'-phosphate enzyme, was investigated. Bioinformatic analyses followed by site-directed mutagenesis, size exclusion chromatography and catalytic activity experiments allowed us to identify Arg118, Phe238 and Phe240 as interfacial residues not essential for transaminase activity but important for dimer-monomer dissociation. The apo and the holo forms of the triple mutant R118A-Mi/F238S-Mi/F240S-Mi display a dimer-monomer equilibrium dissociation constant value at least ̴ 260- and 31-fold larger, respectively, than the corresponding ones of AGT-Mi...
October 5, 2016: Biochimie
Chatree Saensuk, Samart Wanchana, Kiattawee Choowongkomon, Sugunya Wongpornchai, Tippaya Kraithong, Wachiraya Imsabai, Ekawat Chaichoompu, Vinitchan Ruanjaichon, Theerayut Toojinda, Apichart Vanavichit, Siwaret Arikit
Thailand's aromatic coconut (Cocos nucifera L.) is a special type of green dwarf coconut, the liquid endosperm of which is characterized by a pleasant "pandan-like" aroma due to the presence of 2-acetyl-1-pyrroline (2AP). The aim of this study was to perform a de novo assembly of transriptome from C. nucifera endosperm and to identify the gene responsible for 2AP biosynthesis. CnAMADH2 was identified as an ortholog of the rice aromatic gene and a G-to-C substitution found in exon 14 was associated with 2AP content in the aromatic green dwarf coconut accessions...
November 2016: Plant Science: An International Journal of Experimental Plant Biology
Anna Melkov, Raju Baskar, Yehonatan Alcalay, Uri Abdu
Intrinsic cell microtubule (MT) polarity, together with molecular motors and adaptor proteins, determines mitochondrial polarized targeting and MT-dependent transport. In polarized cells, such as neurons, mitochondrial mobility and transport require the regulation of kinesin and dynein by two adaptor proteins, Milton and Miro. Recently, we found that dynein heavy chain 64C (Dhc64C) is the primary motor protein for both anterograde and retrograde transport of mitochondria in the Drosophila bristle. In this study, we revealed that a molecular lesion in the Dhc64C allele that reduced bristle mitochondrial velocity generated a variant that acts as a "slow" dynein in a MT gliding assay, indicative of dynein directly regulating mitochondrial transport...
October 5, 2016: Development
G Shi, S J Li, T T Wang, C M Cheng, Y M Fan, K J Zhu
Recent genetic evidence suggests a robust association of the CARD14 single nucleotide polymorphism rs11652075 (c.C2458T/p.Arg820Trp) and other rare mutations in this gene with psoriasis. To assess whether combined data support the relationship between CARD14 rs11652075 and susceptibility to this disease, we conducted a meta-analysis. PubMed (MEDLINE), EMBASE, Web of Science, and the Cochrane Library were searched for relevant papers published in English. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effect models...
August 19, 2016: Genetics and Molecular Research: GMR
Anna Linderholm, Daisy Spencer, Vincent Battista, Laurent Frantz, Ross Barnett, Robert C Fleischer, Helen F James, Dave Duffy, Jed P Sparks, David R Clements, Leif Andersson, Keith Dobney, Jennifer A Leonard, Greger Larson
Pigs (Sus scrofa) have played an important cultural role in Hawaii since Polynesians first introduced them in approximately AD 1200. Additional varieties of pigs were introduced following Captain Cook's arrival in Hawaii in 1778 and it has been suggested that the current pig population may descend primarily, or even exclusively, from European pigs. Although populations of feral pigs today are an important source of recreational hunting on all of the major islands, they also negatively impact native plants and animals...
September 2016: Royal Society Open Science
Luisa Azevedo, Matthew Mort, Antonio C Costa, Raquel M Silva, Dulce Quelhas, Antonio Amorim, David N Cooper
Understanding the functional sequelae of amino-acid replacements is of fundamental importance in medical genetics. Perhaps, the most intuitive way to assess the potential pathogenicity of a given human missense variant is by measuring the degree of evolutionary conservation of the substituted amino-acid residue, a feature that generally serves as a good proxy metric for the functional/structural importance of that residue. However, the presence of putatively compensated variants as the wild-type alleles in orthologous proteins of other mammalian species not only challenges this classical view of amino-acid essentiality but also precludes the accurate evaluation of the functional impact of this type of missense variant using currently available bioinformatic prediction tools...
October 5, 2016: European Journal of Human Genetics: EJHG
Shio-Shin Jean, Po-Ren Hsueh
OBJECTIVES: To investigate the antimicrobial resistance and assess the molecular characteristics of β-lactamases (ESBLs, AmpC β-lactamases and carbapenemases) among Enterobacteriaceae isolates that caused intra-abdominal infections (IAIs) in patients hospitalized in the Asia-Pacific region during 2008-14. METHODS: Multiplex PCR was used to detect the specific types of β-lactamase in 2893 isolates with MICs of ertapenem >0.5 mg/L. In-hospital acquisition times for most isolates were also delineated...
October 4, 2016: Journal of Antimicrobial Chemotherapy
Roseanne Rosario, Panagiotis Filis, Victoria Tessyman, Hazel Kinnell, Andrew J Childs, Nicola K Gray, Richard A Anderson
Germ cell development and primordial follicle formation during fetal life is critical in establishing the pool of oocytes that subsequently determines the reproductive lifespan of women. Fragile X-associated primary ovarian insufficiency (FXPOI) is caused by inheritance of the FMR1 premutation allele and approximately 20% of women with the premutation allele develop ovarian dysfunction and premature ovarian insufficiency. However, the underlying disease mechanism remains obscure, and a potential role of FMRP in human ovarian development has not been explored...
2016: PloS One
Edward J Romasko, Nora Engel
Genomic imprinting is an epigenetic mechanism that affects a subset of mammalian genes, resulting in monoallelic expression depending on the parental origin of the alleles. Imprinted regions contain regulatory elements that are methylated in the gametes in a sex-specific manner (differentially methylated regions or DMRs). DMRs are present at non-imprinted loci as well, but whereas most regions are equalized after fertilization, methylation at imprinted regions maintains asymmetry. We tested the hypothesis that paternally unmethylated DMRs are occupied by transcription factors (TFs) present during male gametogenesis...
September 30, 2016: G3: Genes—Genomes—Genetics
Catherine Jan, Luca Fumagalli
The parrot family represents one of the bird group with the largest number of endangered species, as a result of habitat destruction and illegal trade. This illicit traffic involves the smuggling of eggs and animals, and the laundering through captive breeding facilities of wild-caught animals. Despite the huge potential of wildlife DNA forensics to determine with conclusive evidence illegal trade, current usage of DNA profiling approaches in parrots has been limited by the lack of suitable molecular markers specifically developed for the focal species and by low cross-species polymorphism...
2016: PeerJ
Uri Rozovski, Srdan Verstovsek, Taghi Manshouri, Vilma Dembitz, Ksenija Bozinovic, Kate Newberry, Ying Zhang, Joseph E Bove, Sherry Pierce, Hagop Kantarjian, Zeev Estrov
In most patients with primary myelofibrosis, one of three mutually exclusive somatic mutations is detected. In approximately 60% of patients, the Janus kinase 2 gene is mutated; in 20%, the calreticulin gene is mutated; and in 5%, the myeloproliferative leukemia virus gene is mutated. Although patients with mutated calreticulin or myeloproliferative leukemia have a favorable outcome and those with none of these mutations have an unfavorable outcome, prognostication based on mutation status is challenging owing to the heterogeneous survival of patients with mutated Janus kinase 2...
September 29, 2016: Haematologica
Fang-Teng Liu, Liang Zhou, Cheng Qiu, Guangfeng Xia, Pei-Qian Zhu, Hong-Liang Luo
PURPOSE: To explore the association between HOTAIR rs4759314 and cancer risk. METHODS: A comprehensive online search was conducted using PubMed, EMBASE, and CNKI databases to identify relevant studies. The case-control studies related to HOTAIR rs4759314 polymorphism and cancer risk were selected according to the inclusion and exclusion criteria. The retrieval time was until November 2015. After extracting the basic data information and performing an evaluation of the quality of the literature, the meta-analysis was performed using STATA 12...
July 2016: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
John P Dowling, Yubo Cai, John Bertin, Peter J Gough, Jianke Zhang
The death receptor, Fas, triggers apoptotic death and is essential for maintaining homeostasis in the peripheral lymphoid organs. RIP1 was originally cloned when searching for Fas-binding proteins and was later shown to associate also with the signaling complex of TNFR1. Although Fas exclusively induces apoptosis, TNFR1 primarily activates the pro-survival/pro-inflammatory NF-κB pathway. Mutations in Fas lead to lymphoproliferative (lpr) diseases, and deletion of TNFR1 results in defective innate immune responses...
2016: Cell Death & Disease
Christopher Smith, Jillian S Parboosingh, Kym M Boycott, Carsten G Bönnemann, Jean K Mah, Ryan E Lamont, A Micheil Innes, Francois P Bernier
Mutations in GLE1 cause two recessive subtypes of Arthrogryposis Multiplex Congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period. GLE1 related AMC has been almost exclusively reported in the Finnish population and is caused by a relatively common pathogenic splicing mutation in that population. Here, we report two non-Finnish brothers with novel compound heterozygous splicing mutations in GLE1, one of whom has survived to 12 years of age...
September 29, 2016: Clinical Genetics
Vinayak Singh, Neeraj Dhar, János Pató, Gaëlle S Kolly, Jana Korduláková, Martin Forbak, Joanna C Evans, Rita Székely, Jan Rybniker, Zuzana Palčeková, Júlia Zemanová, Isabella Santi, François Signorino-Gelo, Liliana Rodrigues, Anthony Vocat, Adrian S Covarrubias, Monica G Rengifo, Kai Johnsson, Sherry Mowbray, Joseph Buechler, Vincent Delorme, Priscille Brodin, Graham W Knott, José A Aínsa, Digby F Warner, György Kéri, Katarína Mikušová, John D McKinney, Stewart T Cole, Valerie Mizrahi, Ruben C Hartkoorn
There is an urgent need to discover new anti-tubercular agents with novel mechanisms of action in order to tackle the scourge of drug-resistant tuberculosis. Here, we report the identification of such a molecule - an AminoPYrimidine-Sulfonamide (APYS1) that has potent, bactericidal activity against M. tuberculosis. Mutations in APYS1-resistant M. tuberculosis mapped exclusively to wag31, a gene that encodes a scaffolding protein thought to orchestrate cell elongation. Recombineering confirmed that a Gln201Arg mutation in Wag31 was sufficient to cause resistance to APYS1, however, neither overexpression nor conditional depletion of wag31 impacted M...
September 28, 2016: Molecular Microbiology
Jing Chen, Bingbing Xie, Yaran Yang, Meng Yang, Chao Liu, Yuexin Lv, Chuguang Chen, Xiu Liu, Xiangdong Fang, Huijuan Wu, Jiangwei Yan
BACKGROUND: Investigation of allele and genotype frequencies of microsatellite loci in various populations is an essential prerequisite in forensic application. AIM: In the present study, we obtained population genetic data and forensic parameters of 39 autosomal Short Tandem Repeats (STRs) loci from Chinese Li ethnic group and estimated the genetic relationships between Li and other reference populations. SUBJECTS AND METHODS: Thirty-nine STR loci, which include D19S433, D5S818, D21S11, D18S51, D6S1043, D3S1358, D13S317, D7S820, D16S539, CSF1PO, Penta D, D2S441, vWA, D8S1179, TPOX, Penta E, TH01, D12S391, D2S1338, FGA, D6S477, D18S535, D19S253, D15S659, D11S2368, D20S470, D1S1656, D22-GATA198B05, D8S1132, D4S2366, D21S1270, D13S325, D9S925, D3S3045, D14S608, D10S1435, D7S3048, D17S1290 and D5S2500, were amplified two multiplex DNA-STR fluorescence detection systems for 189 unrelated healthy individuals of Chinese Li ethnic group...
September 26, 2016: Annals of Human Biology
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