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Embryonic lethal

Jeffrey L Neul, Timothy A Benke, Eric D Marsh, Steven A Skinner, Jonathan Merritt, David N Lieberman, Shannon Standridge, Timothy Feyma, Peter Heydemann, Sarika Peters, Robin Ryther, Mary Jones, Bernhard Suter, Walter E Kaufmann, Daniel G Glaze, Alan K Percy
Mutations in the X-linked gene MECP2 are associated with a severe neurodevelopmental disorder, Rett syndrome (RTT), primarily in girls. It had been suspected that mutations in Methyl-CpG-binding protein 2 (MECP2) led to embryonic lethality in males, however such males have been reported. To enhance understanding of the phenotypic spectrum present in these individuals, we identified 30 males with MECP2 mutations in the RTT Natural History Study databases. A wide phenotypic spectrum was observed, ranging from severe neonatal encephalopathy to cognitive impairment...
December 7, 2018: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
James M Havrilla, Brent S Pedersen, Ryan M Layer, Aaron R Quinlan
Deep catalogs of genetic variation from thousands of humans enable the detection of intraspecies constraint by identifying coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single gene-wide metrics conceal regional constraint variability within each gene. Therefore, we have created a detailed map of constrained coding regions (CCRs) by leveraging variation observed among 123,136 humans from the Genome Aggregation Database. The most constrained CCRs are enriched for pathogenic variants in ClinVar and mutations underlying developmental disorders...
December 10, 2018: Nature Genetics
Ömer Copur, Andrey Gorchakov, Katja Finkl, Mitzi I Kuroda, Jürg Müller
Acetylation of histone H4 at lysine 16 (H4K16) modulates nucleosome-nucleosome interactions and directly affects nucleosome binding by certain proteins. In Drosophila , H4K16 acetylation by the dosage compensation complex subunit Mof is linked to increased transcription of genes on the single X chromosome in males. Here, we analyzed Drosophila containing different H4K16 mutations or lacking Mof protein. An H4K16A mutation causes embryonic lethality in both sexes, whereas an H4K16R mutation permits females to develop into adults but causes lethality in males...
December 10, 2018: Proceedings of the National Academy of Sciences of the United States of America
Takashi Kiuchi, Yudai Sugano, Toru Shimada, Susumu Katsuma
The Masculinizer (Masc) gene encodes a novel lepidopteran-specific protein that controls both masculinization and dosage compensation in the silkworm Bombyx mori. The Masc protein possesses two CCCH-type zinc finger domains (ZFs), a nuclear localization signal, and an 11-amino-acid region that is highly conserved among lepidopteran insects. Using a cell-based assay system, we revealed that two cysteine residues localized in the conserved region, but not ZFs, are required for masculinization. In addition, nuclear localization of the Masc protein is not associated with masculinizing activity...
December 7, 2018: Insect Biochemistry and Molecular Biology
Ying Shao, Hongxia Xiao, Carolina Di Paolo, Björn Deutschmann, Werner Brack, Henner Hollert, Thomas Benjamin Seiler
Water pollution risks to human health and the environment are emerging as serious concerns in the European Union and worldwide. With the aim to achieve good ecological and chemical status of all European water bodies, the "European Water Framework Directive" (WFD) was enacted. With the framework, bioanalytical techniques have been recognized as an important aspect. However, there are limitations to the application of bioassays directly for water quality assessment. Such approaches often fail to identify pollutants of concern, since the defined priority and monitored pollutants often fail to explain the observed toxicity...
November 28, 2018: Water Research
Joshi Stephen, Sateesh Maddirevula, Sheela Nampoothiri, John D Burke, Matthew Herzog, Anju Shukla, Katharina Steindl, Ascia Eskin, Siddaramappa J Patil, Pascal Joset, Hane Lee, Lisa J Garrett, Tadafumi Yokoyama, Nicholas Balanda, Steven P Bodine, Nathanial J Tolman, Patricia M Zerfas, Allison Zheng, Georgia Ramantani, Katta M Girisha, Cecilia Rivas, Pujar V Suresh, Abdel Elkahloun, Hessa S Alsaif, Salma M Wakil, Laila Mahmoud, Rehab Ali, Michaela Prochazkova, Ashok B Kulkarni, Tawfeg Ben-Omran, Dilek Colak, H Douglas Morris, Anita Rauch, Julian A Martinez-Agosto, Stanley F Nelson, Fowzan S Alkuraya, William A Gahl, May Christine V Malicdan
Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals...
December 6, 2018: American Journal of Human Genetics
Wanlin Yang, Kijung Sung, Fengli Zhou, Wei Xu, Robert A Rissman, Jianqing Ding, Chengbiao Wu
Nerve growth factor (NGF) exerts multifaceted functions through different stages of life. A missense mutation (R100W) in the beta-NGF gene was found in hereditary sensory autonomic neuropathy V (HSAN V) patients with severe loss of pain perception but without overt cognitive impairment. To better understand the pathogenesis of HSAN V, we generated the first NGFR100W knock in mouse model for HSAN V. We found that the homozygotes exhibited a postnatal lethal phenotype. A majority of homozygous pups died within the first week...
2018: Frontiers in Aging Neuroscience
Stefan C Materna, Tanvi Sinha, Ralston M Barnes, Kelly Lammerts van Bueren, Brian L Black
MEF2C is a member of the highly conserved MEF2 family of transcription factors and is a key regulator of cardiovascular development. In mice, Mef2c is expressed in the developing heart and vasculature, including the endothelium. Loss of Mef2c function in germline knockout mice leads to early embryonic demise and profound developmental abnormalities in the cardiovascular system. Previous attempts to uncover the cause of embryonic lethality by specifically disrupting Mef2c function in the heart or vasculature failed to recapitulate the global Mef2c knockout phenotype and instead resulted in relatively minor defects that did not compromise viability or result in significant cardiovascular defects...
December 3, 2018: Developmental Biology
Madhav Jagannathan, Yukiko Yamashita
Exploring the mechanisms that cause hybrid incompatibility can illuminate divergent genomic elements between species that may otherwise be cryptic. Recent work shows that uniparental chromosome elimination in hybrids between two frog species triggers a metabolic crisis and embryonic lethality.
December 3, 2018: Developmental Cell
Kei Hiramatsu, Satoshi Abe, Kanako Kazuki, Mitsuhiko Osaki, Naoyo Kajitani, Yuwna Yakura, Mitsuo Oshimura, Yasuhiro Kazuki
Aneuploidy is the gain or loss of a chromosome. Down syndrome or trisomy (Ts) 21 is the most frequent live-born aneuploidy syndrome in humans and extensively studied using model mice. However, there is no available model mouse for other congenital Ts syndromes, possibly because of the lethality of Ts in vivo, resulting in the lack of studies to identify the responsible gene(s) for aneuploid syndromes. Although induced pluripotent stem cells derived from patients are useful to analyse aneuploidy syndromes, there are concerns about differences in the genetic background for comparative studies and clonal variations...
November 30, 2018: Biochemical and Biophysical Research Communications
Ben J Hayes, Hans D Daetwyler
The 1000 Bull Genomes Project is a collection of whole-genome sequences from 2,703 individuals capturing a significant proportion of the world's cattle diversity. So far, 84 million single-nucleotide polymorphisms (SNPs) and 2.5 million small insertion deletions have been identified in the collection, a very high level of genetic diversity. The project has greatly accelerated the identification of deleterious mutations for a range of genetic diseases, as well as for embryonic lethals. The rate of identification of causal mutations for complex traits has been slower, reflecting the typically small effect size of these mutations and the fact that many are likely in as-yet-unannotated regulatory regions...
December 3, 2018: Annual Review of Animal Biosciences
Megan S Rost, Ilya Shestopalov, Yang Liu, Andy H Vo, Catherine E Richter, Sylvia M Emly, Francesca G Barrett, David L Stachura, Michael Holinstat, Leonard I Zon, Jordan A Shavit
The NFE2 transcription factor is expressed in multiple hematopoietic lineages with a well-defined role in regulating megakaryocyte biogenesis and platelet production in mammals. Mice deficient in NFE2 develop severe thrombocytopenia with lethality resulting from neonatal hemorrhage. Recent data in mammals reveal potential differences in embryonic and adult thrombopoiesis. Multiple studies in zebrafish have revealed mechanistic insights into hematopoiesis, although thrombopoiesis has been less studied. Rather than platelets, zebrafish possess thrombocytes, which are nucleated cells with similar functional properties...
December 11, 2018: Blood Advances
Ling Ling, Jingjing Wen, Liang Tao, Mengshu Zhao, Wenhao Ge, Lei Wang, Jianfa Zhang, Dan Weng
Tributyltin (TBT), a widely distributed environmental pollutant, is toxic to animals and human beings. Although its toxicity, especially the immunosuppressive effect, has been reported a lot, the underlying molecular mechanisms are still unclear. In this study, we investigated the mechanisms of TBT-induced cytotoxicity both in vitro and in vivo. TBT induced cell death in both J774A.1 macrophages and mouse bone marrow-derived macrophages (BMDMs) as measured by the LDH and Annexin V-FITC/PI dual staining assays...
November 24, 2018: Chemosphere
Anderson de Oliveira Souza, Carlos Antônio Couto-Lima, Carlos Henrique Rocha Catalão, Nilton Nascimento Santos-Júnior, Júlia Fernanda Dos Santos, Maria Jose Alves da Rocha, Luciane Carla Alberici
Several studies have shown the protective effects of dietary enrichment of omega-3 (ω-3) long-chain fatty acids in several animal models of neurodegenerative diseases. Here we investigate if eicosapentaenoic (EPA) and Docosahexaenoic (DHA) acids (ω-3) protect against neurodegeneration mediated by the exposure to a widely used herbicide Paraquat (PQ) (1,1'-dimethyl-4-4'-bipyridinium dichloride), focusing on mitochondrial metabolism using Drosophila melanogaster as a model. Dietary ingestion of PQ for 3 days resulted in the loss of citrate synthase content, respiratory capacity impairment and exacerbated H2 O2 production per mitochondrial unit related to complex I dysfunction, and high lactate accumulation in fly heads...
November 28, 2018: Neurotoxicology
Fenjie Li, Junjun Ding
Sialylation, or the covalent addition of sialic acid to the terminal end of glycoproteins, is a biologically important modification that is involved in embryonic development, neurodevelopment, reprogramming, oncogenesis and immune responses. In this review, we have given a comprehensive overview of the current literature on the involvement of sialylation in cell fate decision during development, reprogramming and cancer progression. Sialylation is essential for early embryonic development and the deletion of UDP-GlcNAc 2-epimerase, a rate-limiting enzyme in sialic acid biosynthesis, is embryonically lethal...
November 26, 2018: Protein & Cell
Madhulika B Gupta, Thomas Jansson
Mechanistic target of rapamycin (mTOR) signaling functions as a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. mTOR is therefore critical for the growth of most fetal organs and global mTOR deletion is embryonic lethal. This review discusses emerging evidence suggesting that mTOR signaling also has a role as a critical hub in the overall, homeostatic control of fetal growth, adjusting the fetal growth trajectory according to the ability of the maternal supply line to support fetal growth...
November 21, 2018: Biology of Reproduction
Hui Peng, Jing Chen, Yuyun Gao, Jianchao Huo, Chongchong Wang, Yanyan Zhang, Tianfang Xiao
Valosin-containing protein (VCP) is a member of the highly conserved AAA (ATPase associated with a variety of cellular activities) superfamily. A previous study has shown that targeted deletion of Vcp in mice results in early embryonic lethality. The aim of the present study was to analyze the expression and localization of VCP and its function in meiotic arrest of mouse oocytes. Vcp mRNA and protein were expressed in multiple mouse tissues. In the ovary, VCP protein was mainly expressed in oocytes and granulosa cells...
November 21, 2018: Biology of Reproduction
Shahrbanou Hosseini, Bertram Brenig, Jens Tetens, A Reza Sharifi
Ambient temperature during early stages of life has a substantial effect on physiological processes, eliciting phenotypic plasticity during zebrafish developmental stages. Zebrafish are known to possess a noteworthy ability to modify their phenotype in dependence of environmental factors. However, there is a poor understanding of the effects of temperature during embryogenesis, which influences the biological function like survival ability and masculinization in later life. Since the middle embryonic phase (pharyngula period) is genetically the most conserved stage in embryogenesis, it is very susceptible to embryonic lethality in developmental processes of vertebrates...
November 25, 2018: Reproduction in Domestic Animals, Zuchthygiene
Catherine M Mageeney, Michael G Kearse, Brett W Gershman, Caroline E Pritchard, Jennifer M Colquhoun, Vassie C Ware
Duplicated ribosomal protein (RP) genes in the Drosophila melanogaster eRpL22 family encode structurally-divergent and differentially-expressed rRNA-binding RPs. eRpL22 is expressed ubiquitously and eRpL22-like expression is tissue-restricted with highest levels in the adult male germline. We explored paralogue functional equivalence using the GAL4-UAS system for paralogue knockdown or overexpression and a conditional eRpL22-like knockout in a heat- shock flippase/FRT line. Ubiquitous eRpL22 knockdown with Actin-GAL4 resulted in embryonic lethality, confirming eRpL22 essentiality...
November 22, 2018: Fly
Yih-Lin Chen, Lih-Jen Chen, Chiung-Chih Chu, Po-Kai Huang, Jie-Ru Wen, Hsou-Min Li
The two-membrane envelope is a defining feature of chloroplasts. Chloroplasts evolved from a Gram-negative cyanobacterial endosymbiont. During evolution, genes of the endosymbiont have been transferred to the host nuclear genome. Most chloroplast proteins are synthesized in the cytosol as higher-molecular-mass preproteins with an N-terminal transit peptide. Preproteins are transported into chloroplasts by the TOC and TIC (translocons at the outer- and inner-envelope membranes of chloroplasts, respectively) machineries1,2 , but how TOC and TIC are assembled together is unknown...
November 21, 2018: Nature
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