Genomes and Genes
Summary: A nitrosourea compound with alkylating, carcinogenic, and mutagenic properties.
- Gil Perotin S, Marin Husstege M, Li J, Soriano Navarro M, Zindy F, Roussel M, et al. Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors. J Neurosci. 2006;26:1107-16 pubmed..Together, these findings provide a cellular mechanism for how the slow-proliferating SVZ cells can give rise to glial tumors in the adult brain. ..
- Acevedo Arozena A, Wells S, Potter P, Kelly M, Cox R, Brown S. ENU mutagenesis, a way forward to understand gene function. Annu Rev Genomics Hum Genet. 2008;9:49-69 pubmed..N-ethyl-N-nitrosourea (ENU) mutagenesis has been widely used for both approaches to generate mouse mutants. Here we review progress in ENU mutagenesis screening, with an emphasis on creating mouse models for human disorders. ..
- van Boxtel R, Toonen P, van Roekel H, Verheul M, Smits B, Korving J, et al. Lack of DNA mismatch repair protein MSH6 in the rat results in hereditary non-polyposis colorectal cancer-like tumorigenesis. Carcinogenesis. 2008;29:1290-7 pubmed publisher..The MSH6 knockout rat complements existing models for studying genetic instable tumorigenesis as it provides experimental opportunities that are not available or suboptimal in current models. ..
- Georgel P, Du X, Hoebe K, Beutler B. ENU mutagenesis in mice. Methods Mol Biol. 2008;415:1-16 pubmed publisher..In this chapter, we will provide a practical guideline for performing germline mutagenesis in mice. In particular, we will focus on the application of this technology to identify genes that are essential to innate immune defense. ..
- Katayama K, Ueno M, Yamauchi H, Nagata T, Nakayama H, Doi K. Ethylnitrosourea induces neural progenitor cell apoptosis after S-phase accumulation in a p53-dependent manner. Neurobiol Dis. 2005;18:218-25 pubmed..In this study, immediately after the administration of ethylnitrosourea (ENU), an alkylating agent, an accumulation of neural progenitor cells in the S phase was observed...
- Takahasi K, Sakuraba Y, Gondo Y. Mutational pattern and frequency of induced nucleotide changes in mouse ENU mutagenesis. BMC Mol Biol. 2007;8:52 pubmed
- Aigner B, Rathkolb B, Mohr M, Klempt M, Hrabe de Angelis M, Wolf E. Generation of ENU-induced mouse mutants with hypocholesterolemia: novel tools for dissecting plasma lipoprotein homeostasis. Lipids. 2007;42:731-7 pubmed..Such findings may be subsequently used for humans and other species. ..
- Ching Y, Munroe R, Moran J, Barker A, Mauceli E, Fennell T, et al. High resolution mapping and positional cloning of ENU-induced mutations in the Rw region of mouse chromosome 5. BMC Genet. 2010;11:106 pubmed publisher..This collection of alleles contributes to the goal of assigning biological functions to all known genes, as well as identifying novel functional elements that would be missed by reverse genetic approaches. ..
- Noveroske J, Hardy R, Dapper J, Vogel H, Justice M. A new ENU-induced allele of mouse quaking causes severe CNS dysmyelination. Mamm Genome. 2005;16:672-82 pubmed..Because the qk(v) allele is a large deletion that affects the expression of three genes, the new neurologic qk(e5) allele is an important addition to this allelic series. ..
- Caspary T, Anderson K. Uncovering the uncharacterized and unexpected: unbiased phenotype-driven screens in the mouse. Dev Dyn. 2006;235:2412-23 pubmed..As the efficiency of sequencing and mutation detection continues to improve, it is likely that forward genetic screens will provide an even more important part of the repertoire of mouse genetics in the future. ..
- Nguyen N, Judd L, Kalantzis A, Whittle B, Giraud A, van Driel I. Random mutagenesis of the mouse genome: a strategy for discovering gene function and the molecular basis of disease. Am J Physiol Gastrointest Liver Physiol. 2011;300:G1-11 pubmed publisher..This review examines the strategies and tools used in ENU mutagenesis screens to efficiently generate and identify functional mutations. ..
- Abe K, Fuchs H, Lisse T, Hans W, Hrabe de Angelis M. New ENU-induced semidominant mutation, Ali18, causes inflammatory arthritis, dermatitis, and osteoporosis in the mouse. Mamm Genome. 2006;17:915-26 pubmed
- Gadjeva V, Tolekova A, Vasileva M. Effect of the spin-labelled 1-ethyl-1-nitrosourea on CCNU-induced oxidative liver injury. Pharmazie. 2007;62:608-13 pubmed..This protective effect is through the scavenging of *O2- and by an increased production of *NO. Thus, a potential for developing new combination chemotherapy in cancer is seen. ..
- Arnold C, Barnes M, Berger M, Blasius A, Brandl K, Croker B, et al. ENU-induced phenovariance in mice: inferences from 587 mutations. BMC Res Notes. 2012;5:577 pubmed publisher..These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice. ..
- Michaud E, Culiat C, Klebig M, Barker P, Cain K, Carpenter D, et al. Efficient gene-driven germ-line point mutagenesis of C57BL/6J mice. BMC Genomics. 2005;6:164 pubmed..The ability of ENU to induce mutations that cause various types of changes in proteins will provide additional insights into the functions of mammalian proteins that may not be detectable by knockout mutations. ..
- Hilton J, Lewis M, Grati M, Ingham N, Pearson S, Laskowski R, et al. Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice. Genome Biol. 2011;12:R90 pubmed publisher..Most importantly, the power of exome resequencing to identify ENU-induced mutations without a mapped gene locus is illustrated. ..
- Hoebe K, Beutler B. Forward genetic analysis of TLR-signaling pathways: an evaluation. Adv Drug Deliv Rev. 2008;60:824-9 pubmed publisher..Here we review some of the more important insights developed from this approach and discuss its prospects. ..
- Aigner B, Rathkolb B, Klaften M, Sedlmeier R, Klempt M, Wagner S, et al. Generation of N-ethyl-N-nitrosourea-induced mouse mutants with deviations in plasma enzyme activities as novel organ-specific disease models. Exp Physiol. 2009;94:412-21 pubmed publisher..The mouse mutants with abnormal plasma enzyme activities recovered in the Munich ENU project are novel tools for the systematic dissection of the pathogenesis of organ diseases. ..
- Augustin M, Sedlmeier R, Peters T, Huffstadt U, Kochmann E, Simon D, et al. Efficient and fast targeted production of murine models based on ENU mutagenesis. Mamm Genome. 2005;16:405-13 pubmed..We conclude that ENU-based targeted mutagenesis is a powerful tool for the fast and high-throughput production of murine gene-specific models for biomedical research. ..
- Fernandez L, Marchuk D, Moran J, Beier D, Rockman H. An N-ethyl-N-nitrosourea mutagenesis recessive screen identifies two candidate regions for murine cardiomyopathy that map to chromosomes 1 and 15. Mamm Genome. 2009;20:296-304 pubmed publisher..The identification of the genes responsible for the observed phenotype in these families will be strong candidates for disease-causing or disease-modifying genes in patients with heart failure. ..
- Lee M, Kim J, Kim Y, Cho J, Cho K, Song C, et al. Characteristics of ethylnitrosourea-induced cataracts. Curr Eye Res. 2009;34:360-8 pubmed publisherThis study analyzed genes associated with the morphology and regulation of ethylnitrosourea (ENU)-induced cataract mouse...
- Grosse J, Tarnow P, Römpler H, Schneider B, Sedlmeier R, Huffstadt U, et al. N-ethyl-N-nitrosourea-based generation of mouse models for mutant G protein-coupled receptors. Physiol Genomics. 2006;26:209-17 pubmed..Our technology described herein has the potential to provide mouse models for a GPCR dysfunction of choice within <4 mo and can be extended to other gene classes of interest. ..
- Sakuraba Y, Sezutsu H, Takahasi K, Tsuchihashi K, Ichikawa R, Fujimoto N, et al. Molecular characterization of ENU mouse mutagenesis and archives. Biochem Biophys Res Commun. 2005;336:609-16 pubmed..The base-substitution spectra in this study were different from those of the phenotype-based mutagenesis. The ENU-based gene-driven mutagenesis in the mouse now becomes feasible and practical. ..
- Achilli F, Bros Facer V, Williams H, Banks G, AlQatari M, Chia R, et al. An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy. Dis Model Mech. 2009;2:359-73 pubmed publisher
- Arnold C, Xia Y, Lin P, Ross C, Schwander M, Smart N, et al. Rapid identification of a disease allele in mouse through whole genome sequencing and bulk segregation analysis. Genetics. 2011;187:633-41 pubmed publisher..Our study demonstrates the speed and utility of whole genome sequencing coupled with low resolution meiotic mapping as a means of identifying causative mutations induced by ENU. ..
- Hong C, Tsai P, Cheng C, Chou C, Jheng H, Chuang Y, et al. ENU mutagenesis identifies mice with morbid obesity and severe hyperinsulinemia caused by a novel mutation in leptin. PLoS ONE. 2010;5:e15333 pubmed publisher..The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome. ..
- Clark A, Goldowitz D, Takahashi J, Vitaterna M, Siepka S, Peters L, et al. Implementing large-scale ENU mutagenesis screens in North America. Genetica. 2004;122:51-64 pubmed..The purpose of this article is to highlight the new projects in North America that are focused on isolating mouse mutations after ENU mutagenesis and phenotype screening. ..
- Furuse T, Wada Y, Hattori K, Yamada I, Kushida T, Shibukawa Y, et al. Phenotypic characterization of a new Grin1 mutant mouse generated by ENU mutagenesis. Eur J Neurosci. 2010;31:1281-91 pubmed publisher..The results of immunohistochemical and biochemical analyses suggested that impaired interaction between the glutamatergic pathway and dopaminergic pathway may underlie the behavioral phenotypes of the Grin1(Rgsc174) mutant. ..
- Feitsma H, de Bruijn E, van de Belt J, Nijman I, Cuppen E. Mismatch repair deficiency does not enhance ENU mutagenesis in the zebrafish germ line. Mutagenesis. 2008;23:325-9 pubmed publisher..Alternatively, the MMR system in the zebrafish germ line may be saturated very rapidly, thereby having a limited effect on high-dose ENU mutagenesis. ..
- Cook M, Dunning J, Wiley R, Chesler E, Johnson D, Miller D, et al. Neurobehavioral mutants identified in an ENU-mutagenesis project. Mamm Genome. 2007;18:559-72 pubmed..e., behavioral and genetic mapping studies) of mutants is in progress with the ultimate goal of identification of novel genes and mouse models relevant to human disorders as well as the identification of novel therapeutic targets. ..
- Russell L, Hunsicker P, Russell W. Comparison of the genetic effects of equimolar doses of ENU and MNU: while the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia. Mutat Res. 2007;616:181-95 pubmedMutagenic, reproductive, and toxicity effects of two closely related chemicals, ethylnitrosourea (ENU) and methylnitrosourea (MNU), were compared at equimolar and near-equimolar doses in the mouse specific-locus test in a screen of all ..
- Furuse T, Yamada I, Kushida T, Masuya H, Miura I, Kaneda H, et al. Behavioral and neuromorphological characterization of a novel Tuba1 mutant mouse. Behav Brain Res. 2012;227:167-74 pubmed publisher..The results of a behavioral pharmacological analysis using methylphenidate and morphological analyses of embryonic and adult brains suggested that Tuba1(Rgsc1736) is a novel animal model for neurodevelopmental disorders. ..
- Beier D, Herron B. Genetic mapping and ENU mutagenesis. Genetica. 2004;122:65-9 pubmed..Determination of the map position of a mutation early in its characterization can be extremely useful. We describe how the use of interval haplotype analysis can facilitate this with even small numbers of affected progeny. ..
- Hughes M, Anderson N, Maltby S, Wong J, Berberovic Z, Birkenmeier C, et al. A novel ENU-generated truncation mutation lacking the spectrin-binding and C-terminal regulatory domains of Ank1 models severe hemolytic hereditary spherocytosis. Exp Hematol. 2011;39:305-20, 320.e1-2 pubmed publisher..The Ank1(E924X) strain provides a novel tool to study Ank1 and model HS. ..
- Keays D, Clark T, Flint J. Estimating the number of coding mutations in genotypic- and phenotypic-driven N-ethyl-N-nitrosourea (ENU) screens. Mamm Genome. 2006;17:230-8 pubmed..002). Where mutants are identified by genotypic methods, we show that backcrossing in the absence of marker-assisted selection is an inefficient means of eliminating linked confounding mutations. ..
- Xu X, Kedlaya R, Higuchi H, Ikeda S, Justice M, Setaluri V, et al. Mutation in archain 1, a subunit of COPI coatomer complex, causes diluted coat color and Purkinje cell degeneration. PLoS Genet. 2010;6:e1000956 pubmed publisher..Our study documents for the first time the physiological consequences of the impairment of the ARCN1 function in the whole animal and demonstrates a direct association between ARCN1 and neurodegeneration. ..
- Hardisty Hughes R, Parker A, Brown S. A hearing and vestibular phenotyping pipeline to identify mouse mutants with hearing impairment. Nat Protoc. 2010;5:177-90 pubmed publisher..5 h per mouse. These protocols have been applied for the identification of mouse models of human deafness and are a key component for investigating the genes and genetic pathways involved in hereditary deafness. ..
- Concepcion D, Seburn K, Wen G, Frankel W, Hamilton B. Mutation rate and predicted phenotypic target sizes in ethylnitrosourea-treated mice. Genetics. 2004;168:953-9 pubmed..To address these questions, we sequenced approximately 9.6 Mb of DNA from G1 progeny of ethylnitrosourea-treated mice in a large, broad-spectrum screen...
- Culiat C, Klebig M, Liu Z, Monroe H, Stanford B, Desai J, et al. Identification of mutations from phenotype-driven ENU mutagenesis in mouse chromosome 7. Mamm Genome. 2005;16:555-66 pubmed..Our data demonstrate that rapid mutation scanning with TGCE, followed by sequence verification only of detected positives, is an efficient approach to the identification of point mutations in the mouse genome. ..
- Smits B, Mudde J, van de Belt J, Verheul M, Olivier J, Homberg J, et al. Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis. Pharmacogenet Genomics. 2006;16:159-69 pubmed..The resulting induced rat models will be powerful tools for studying many aspects of a wide variety of human diseases. ..
- Puk O, Dalke C, Calzada Wack J, Ahmad N, Klaften M, Wagner S, et al. Reduced corneal thickness and enlarged anterior chamber in a novel ColVIIIa2G257D mutant mouse. Invest Ophthalmol Vis Sci. 2009;50:5653-61 pubmed publisher..The results of this study suggest that a functional collagen VIII alpha2 is essential for the correct assembly of the Descemet's membrane and for corneal stability. Aca23 might be used as a novel model for keratoglobus. ..
- Zhang Z, Alpert D, Francis R, Chatterjee B, Yu Q, Tansey T, et al. Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy. Proc Natl Acad Sci U S A. 2009;106:3219-24 pubmed publisher..Overall, through the recovery of an ENU-induced mutation, we uncovered Megf8 as an essential regulator of left-right patterning. ..
- Harris T, Marquez B, Suarez S, Schimenti J. Sperm motility defects and infertility in male mice with a mutation in Nsun7, a member of the Sun domain-containing family of putative RNA methyltransferases. Biol Reprod. 2007;77:376-82 pubmed..Therefore, Ste5Jcs1 mutation uncovers a previously unrecognized biological process in sperm that underscores the functional compartmentalization of the midpiece and principal piece of the flagellum. ..
- Barbaric I, Perry M, Dear T, Rodrigues Da Costa A, Salopek D, Marusic A, et al. An ENU-induced mutation in the Ankrd11 gene results in an osteopenia-like phenotype in the mouse mutant Yoda. Physiol Genomics. 2008;32:311-21 pubmed..This gene has not been previously associated with bone metabolism and, thus, identifies a novel genetic regulator of bone homeostasis. ..
- Lewis M, Quint E, Glazier A, Fuchs H, de Angelis M, Langford C, et al. An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nat Genet. 2009;41:614-8 pubmed publisher..This is the first microRNA found associated with deafness, and diminuendo represents a model for understanding and potentially moderating progressive hair cell degeneration in hearing loss more generally. ..
- Aigner B, Rathkolb B, Herbach N, Hrabe de Angelis M, Wanke R, Wolf E. Diabetes models by screen for hyperglycemia in phenotype-driven ENU mouse mutagenesis projects. Am J Physiol Endocrinol Metab. 2008;294:E232-40 pubmed
- Bull K, Rimmer A, Siggs O, Miosge L, Roots C, Enders A, et al. Unlocking the bottleneck in forward genetics using whole-genome sequencing and identity by descent to isolate causative mutations. PLoS Genet. 2013;9:e1003219 pubmed publisher..The introduction of this approach will accelerate the discovery of causal variants, permit broader and more informative lethal screens to be used, reduce animal costs, and herald a new era for ENU mutagenesis. ..
- Masuya H, Sezutsu H, Sakuraba Y, Sagai T, Hosoya M, Kaneda H, et al. A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud. Genomics. 2007;89:207-14 pubmed..Thus, this study shows that gene-driven screening for ENU-induced mutations is an effective approach for exploring the function of conserved, noncoding sequences and potential cis-regulatory elements. ..
- Crozat K, Georgel P, Rutschmann S, Mann N, Du X, Hoebe K, et al. Analysis of the MCMV resistome by ENU mutagenesis. Mamm Genome. 2006;17:398-406 pubmed
- Zarbalis K, Siegenthaler J, Choe Y, May S, Peterson A, Pleasure S. Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development. Proc Natl Acad Sci U S A. 2007;104:14002-7 pubmed..Furthermore, we provide evidence that defects in meningeal differentiation can lead to severe cortical dysplasia. ..
- Longo Guess C, Gagnon L, Bergstrom D, Johnson K. A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9. Hear Res. 2007;234:21-8 pubmed
- Cordes S. N-ethyl-N-nitrosourea mutagenesis: boarding the mouse mutant express. Microbiol Mol Biol Rev. 2005;69:426-39 pubmed