RESUMEN
Hfi is a dominant cataract mutation where heterozygotes show hydropic lens fibers and homozygotes show total lens opacity. The Hfi locus was mapped to the distal part of mouse chromosome 10 close to the major intrinsic protein (Mip), which is expressed only in cell membranes of lens fibers. Molecular analysis of Mip revealed a 76-bp deletion that resulted in exon 2 skipping in Mip mRNA. In Hfi/Hfi this deletion resulted in a complete absence of the wildtype Mip. In contrast, Hfi/+ animals had the same amount of wildtype Mip as +/+. Results from pulse-chase expression studies excluded hetero-oligomerization of wildtype and mutant Mip as a possible mechanism for cataract formation in the Hfi/+. We propose that the cataract phenotype in the Hfi heterozygote mutant is due to a detrimental gain of function by the mutant Mip resulting in either cytotoxicity or disruption in processing of other proteins important for the lens. Cataract formation in the Hfi/Hfi mouse is probably a combined result of both the complete loss of wildtype Mip and a gain of function of the mutant Mip.
Asunto(s)
Catarata/genética , Proteínas del Ojo/genética , Glicoproteínas de Membrana , Animales , Animales Recién Nacidos , Acuaporinas , Western Blotting , Catarata/patología , Línea Celular , Mapeo Cromosómico , ADN/química , ADN/genética , Análisis Mutacional de ADN , Proteínas del Ojo/metabolismo , Femenino , Expresión Génica , Genes Dominantes , Genotipo , Humanos , Cristalino/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Mutantes , Mutación , Oocitos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Eliminación de Secuencia , XenopusRESUMEN
Phenotype-based mutagenesis experiments will increase the mouse mutant resource, generating mutations at previously unmarked loci as well as extending the allelic series at known loci. Mapping, molecular characterization, and phenotypic analysis of nine independent Pax6 mutations of the mouse recovered in mutagenesis experiments is presented. Seven mutations result in premature termination of translation and all express phenotypes characteristic of null alleles, suggesting that Pax6 function requires all domains to be intact. Of major interest is the identification of two possible hypomorph mutations: Heterozygotes express less severe phenotypes and homozygotes develop rudimentary eyes and nasal processes and survive up to 36 hr after birth. Pax6(4Neu) results in an amino acid substitution within the third helix of the homeodomain. Three-dimensional modeling indicates that the amino acid substitution interrupts the homeodomain recognition alpha-helix, which is critical for DNA binding. Whereas cooperative dimer binding of the mutant homeodomain to a paired-class DNA target sequence was eliminated, weak monomer binding was observed. Thus, a residual function of the mutated homeodomain may explain the hypomorphic nature of the Pax6(4Neu) allele. Pax6(7Neu) is a base pair substitution in the Kozak sequence and results in a reduced level of Pax6 translation product. The Pax6(4Neu) and Pax6(7Neu) alleles may be very useful for gene-dosage studies.
Asunto(s)
Proteínas de Homeodominio/genética , Alelos , Animales , Western Blotting , Mapeo Cromosómico , Cruzamientos Genéticos , ADN/metabolismo , ADN Complementario/metabolismo , Bases de Datos como Asunto , Electroforesis en Gel de Poliacrilamida , Exones , Ojo/embriología , Proteínas del Ojo , Dosificación de Gen , Heterocigoto , Homocigoto , Intrones , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Mutación , Nariz/embriología , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box , Fenotipo , Biosíntesis de Proteínas , Estructura Terciaria de Proteína , Proteínas Represoras , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
The germline supermutagen, N-ethyl-N-nitrosourea (ENU), has a variety of effects on mice. ENU is a toxin and carcinogen as well as a mutagen, and strains differ in their susceptibility to its effects. Therefore, it is necessary to determine an appropriate mutagenic, non-toxic dose of ENU for strains that are to be used in experiments. In order to provide some guidance, we have compiled data from a number of laboratories that have exposed male mice from inbred and non-inbred strains or their F(1) hybrids to ENU. The results show that most F(1) hybrid animals tolerate ENU well, but that inbred strains of mice vary in their longevity and in their ability to recover fertility after treatment with ENU.
Asunto(s)
Etilnitrosourea/farmacología , Ratones/genética , Animales , Relación Dosis-Respuesta a Droga , Etilnitrosourea/toxicidad , Hibridación Genética , Infertilidad Masculina/inducido químicamente , Inyecciones Intraperitoneales , Masculino , Ratones Endogámicos , Ratones MutantesRESUMEN
We have summarized our extensive series of mutagenesis experiments to isolate dominant mutations in the mouse that express eye morphological defects. Thirty-two experimental groups in which parental mice were exposed to chemical mutagens or irradiation and a historical control group of the laboratory are presented. The largest series of experiments included parental exposure to ethylnitrosourea or irradiation. A total of 203 dominant mutants were confirmed among 456,890 offspring screened, which represents one of the largest collections of mutations in the mouse affecting one organ following a systematic screen of offspring of mutagenized animals. The largest group of mutations (92) was recovered in offspring of parental mice exposed to ethylnitrosourea. The second largest group of mutations (62) was recovered in irradiation experiments. Fifty-six mutations recovered in ethylnitrosourea experiments have been mapped to 22 loci. The affected genes have been identified for a number of the recovered mutations including Cryga, Crygb, Cgyge, Pax6, Pax2, Mitf, Lim2, and Cx50. On the basis of our experiences, a number of considerations when undertaking such screens are discussed, including a) choice of mutagen, b) experimental design, and c) the criteria for such experiments to ensure that mutations at novel loci will be recovered.
Asunto(s)
Enfermedades Hereditarias del Ojo/genética , Genes Dominantes , Ratones/genética , Animales , Mapeo Cromosómico , Cruzamientos Genéticos , Modelos Animales de Enfermedad , Etilnitrosourea , Pruebas Genéticas , Ratones Endogámicos , Mutagénesis , Mutágenos , Fenotipo , Genética de RadiaciónRESUMEN
The radiation-induced germ cell mutation rate has been investigated in two species of mammals. Mice and golden hamsters of both sexes were exposed to 2 + 2 Gy gamma-irradiation with a 24 h fractionation interval and mated to untreated partners. In mice, specific locus mutations were examined as positive controls and the obtained mutation rates (per locus and gamete x10(-5)) were 51.4, 10.1, 13.6 and 17.4 for irradiated post-spermatogonia, spermatogonia and 1-7 and >7 days post-treatment oocytes, respectively. Offspring of mice and golden hamsters were screened for activity alterations of 10 erythrocyte enzymes coded by at least 14 loci. The observed mutation rates per locus per gamete x10(-5) for treated post-spermatogonial stages, spermatogonia and oocytes 1-7 and >7 days post-treatment were 6.5, 1.5, 8.8 and 7.0, respectively, for mice and 16.7, 0, 7.6 and 0, respectively, for golden hamsters. There is a significant difference for mutation rates in mouse oocytes 1-7 days post-treatment compared with the control. No differences in the frequencies of mutations in the various germ cell stages could be observed between mice and golden hamsters. A critical assumption for the extrapolation of experimental mutagenesis studies to humans is that no species effects exist in sensitivity to mutation induction by irradiation. Our results do not contradict this assumption.
Asunto(s)
Rayos gamma , Células Germinativas/enzimología , Células Germinativas/efectos de la radiación , Exposición Paterna/efectos adversos , Efectos Tardíos de la Exposición Prenatal , Animales , Cricetinae , Eritrocitos/enzimología , Padre , Femenino , Células Germinativas/citología , Masculino , Mesocricetus , Ratones , Ratones Endogámicos , Pruebas de Mutagenicidad , Mutación , Embarazo , Especificidad de la EspecieRESUMEN
A number of murine cataract mutations have been localized to chromosome 1 close to the gamma-crystallin gene cluster (Cryg) (Everett et al., 1994, Genomics 20: 429-434; Löster et al., 1994, Genomics 23: 240-242). Based on the size of the mapping or allelism tests they have not been shown to be genetically distinct and have been assigned to locus symbol Cat2. Here we assign three mutations to the respective gamma-crystallin gene. Using a systematic candidate gene approach to analyze the entire Cryg cluster, an A-->G transition was found in exon 2 of Cryga for the ENU-436 mutation and is designated Cryga1Neu. The mutant allele Crygbnop (formerly Cat2(nop)) is caused by a replacement of 11 bp by 4 bp in the third exon of Crygb, while a C-->G transversion in exon 3 of Cryge has been found for the Cryget (formerly Cat2(t)) mutation. For the mutation Cryga1Neu, an Asp-->Gly exchange is deduced, whereas the mutations Crygbnop and Cryget lead to the formation of in-frame stop codons and give rise to truncated proteins of 144 and 143 amino acids, respectively. The effects of the mutations upon gamma-crystallin structure are likely to be quite different. The Cryga1Neu mutation is expected to affect the link between Greek-key motifs 2 and 3, whereas both Crygbnop and Cryget mutations are supposed to truncate the fourth Greek-key motif. All three mutations are predicted to alter protein folding of the gamma-crystallins and result in lens cataract, but the phenotype for each is quite distinctive.
Asunto(s)
Catarata/genética , Cristalinas/genética , Genes/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Cartilla de ADN , Femenino , Amplificación de Genes , Eliminación de Gen , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Mutantes , Datos de Secuencia Molecular , Familia de Multigenes/genética , Mutagénesis Insercional , Mutación/genética , Mutación Puntual , Reacción en Cadena de la Polimerasa , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido NucleicoRESUMEN
PURPOSE: Cat4a, one of four mutant alleles at the mouse Cat4 locus, causes central corneal opacity and anterior polar cataract in heterozygotes and microphthalmia in homozygotes. The Cat4 locus has been mapped to chromosome 8, 31 cM from the centromere. In this study ocular development of Cat4a mutant mice was investigated to characterize the defects in eye morphogenesis. METHODS: Serial sections from eyes of wild-type, heterozygous, and homozygous littermates were examined by means of light microscopy at selected intervals from embryonic day 11 to postnatal day 1. Eyes of adult heterozygous and homozygous mice also were evaluated histologically. RESULTS: Failure of separation of the lens vesicle from the surface ectoderm was the earliest structural defect observed. In heterozygous embryos, the abnormality was limited to persistent connection of the anterior pole of the lens to the cornea. Adult heterozygotes had defects in the central corneal stroma and endothelium and anterior polar cataracts with or without keratolenticular adhesion. In homozygous embryos, the persistent connection of lens to surface ectoderm was associated with aborted lens development, failure of closure of the optic fissure, and impairment of growth of the eyecup. Microphthalmic eyes of adult homozygous mice had a poorly developed cornea, and the anterior chamber and vitreous compartment were absent. An extensively folded retina and remnants of a degenerated lens filled the interior of the globe. CONCLUSIONS: A developmental defect inhibits separation of the lens vesicle from surface ectoderm in mice heterozygous or homozygous for the Cat4a mutation. In homozygotes subsequent lens and eye morphogenesis are also severely affected. Cat4a shows phenotypical similarity to several other independent mouse mutations including Small eye, a mutation of the Pax6 gene. Cat4 may be one of several genes involved in a common developmental path and may be part of the Pax6-regulated gene cascade governing eye morphogenesis.
Asunto(s)
Catarata/genética , Cromosomas/genética , Anomalías del Ojo/genética , Ojo/embriología , Mutación , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Animales , Segmento Anterior del Ojo/anomalías , Segmento Anterior del Ojo/embriología , Segmento Anterior del Ojo/patología , Catarata/patología , Mapeo Cromosómico , Ojo/patología , Anomalías del Ojo/patología , Femenino , Cristalino/anomalías , Cristalino/embriología , Cristalino/patología , Ratones , Ratones Endogámicos C3H , Ratones Mutantes , Morfogénesis , EmbarazoRESUMEN
Ifosfamide induced dominant lethal mutations in spermatozoa of mice at doses of 200 and 300 mg/kg and in spermatids and spermatocytes at 600 mg/kg. The highest dose also induced specific-locus mutations in post-spermatogonial germ-cell stages of mice but not in spermatogonial stem cells. The nature of the induced mutations suggests they are intergenic. The spermatogenic specificity of ifosfamide in mouse germ cells is similar to that of the structurally related cytostatic drugs cyclophosphamide and trofosfamide. Due to the post-spermatogonial germ cell specificity of ifosfamide, the genetic risk is limited to a few weeks after exposure.
Asunto(s)
Genes Letales/genética , Ifosfamida/toxicidad , Mutación/genética , Animales , Ciclofosfamida/análogos & derivados , Ciclofosfamida/toxicidad , Genes Dominantes/genética , Células Germinativas/citología , Células Germinativas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Mutágenos/farmacología , Espermatozoides/citología , Espermatozoides/efectos de los fármacosRESUMEN
The occurrence of homozygous-viable dilute-short ear (Myo5a-Bmp5) double mutants in mouse specific locus mutation experiments has generally been assumed to be the result of double non-disjunction such that the mutant inherits two copies of chromosome 9 carrying the recessive alleles from the test-stock. A homozygous viable Myo5a-Bmp5 double mutant was recovered recently in our laboratory. We were able to genetically analyse both the Myo5a-Bmp5 region and proximal and distal markers in the original mutant as well as in offspring of the original mutant. Our results indicate the mutational event to be due to mitotic recombination and not double non-disjunction.
Asunto(s)
Proteínas Morfogenéticas Óseas/genética , Proteínas Fúngicas/genética , Proteínas de Filamentos Intermediarios/genética , Pérdida de Heterocigocidad/genética , Mitosis/genética , Cadenas Pesadas de Miosina , Miosina Tipo I , Miosina Tipo V , Miosinas/genética , Proteínas de Saccharomyces cerevisiae , Alelos , Animales , Proteína Morfogenética Ósea 5 , Cromosomas/genética , Cruzamientos Genéticos , Femenino , Marcadores Genéticos/genética , Haplotipos/genética , Ratones , Ratones Endogámicos , Mutación/genética , No Disyunción Genética , Recombinación Genética/genéticaRESUMEN
PURPOSE: To characterize the mouse cataract mutation Coc. METHODS: Coc is an X-radiation-induced autosomal dominant cataract mutation maintained on a murine C3H inbred strain. The affected heterozygotes were outcrossed to C57BL/6, and (C3H Coc/+ x C57BL/6) mice that were Coc/+ were then backcrossed to C57BL/6 to generate a panel of 103 progeny for mapping. For linkage analysis, microsatellites from each autosome were selected. The maximum distance between markers was 30 centimorgans (cM). RESULTS: The initial genome-wide screen of 14 backcrossed progeny indicated that the Coc locus resides on chromosome 16. Further mapping with additional markers from chromosome 16 for all 103 backcrossed progeny positioned Coc between markers D16Mit134 and D16Mit63. This region is syntenic to human chromosome 3. CONCLUSIONS: Mapping of the Coc locus to mouse chromosome 16 provides the positional information necessary to identify the candidate gene responsible for the Coc phenotype. The molecular characterization of the gene disrupted in the Coc mutation will provide insight into the mechanisms involved in cataract formation.
Asunto(s)
Catarata/genética , Mapeo Cromosómico , Cromosomas/genética , Mutación/genética , Animales , Catarata/etiología , Catarata/patología , Femenino , Cristalino/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Repeticiones de Microsatélite , Fenotipo , Traumatismos Experimentales por Radiación/etiología , Traumatismos Experimentales por Radiación/patologíaRESUMEN
A new mutation at the locus encoding the mast cell growth factor (Mgf) is described and designated as MgfSl-3Neu. Homozygous mutants have a light grey fur, sometimes with white patches. Homozygotes are fertile, but with reduced litter size, when mated inter se. Analysis of haematological parameters indicated no difference between mutant and wild-type mice. Sequence analysis of the cDNA obtained from the brain of homozygous mutants revealed an A-->G exchange at position 400 leading to a predicted amino acid exchange from Asn-->Leu at position 122. As a consequence of the predicted amino acid exchange an extension of the alpha-helical context and a decreased hydropathicity of the region at positions 101-125 can be deduced. This single amino acid exchange is outside of the known important domains of MGF and explains the weak phenotype of MgfSl-3Neu.
Asunto(s)
Alelos , Color del Cabello/genética , Mutación Puntual/genética , Factor de Células Madre/genética , Animales , Cruzamientos Genéticos , Análisis Mutacional de ADN , Exones/genética , Genes/genética , Masculino , Ratones , Datos de Secuencia Molecular , Fenotipo , Factor de Células Madre/química , Relación Estructura-ActividadRESUMEN
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) induced dominant lethal and specific-locus mutations in male mice. For both compounds the germ cell stage sensitive to the induction of dominant lethal mutations was dose dependent. A dose of 5 mg BCNU per kg b.wt. induced dominant lethal mutations primarily in spermatocytes, whereas higher doses of BCNU induced dominant lethals in spermatids and spermatocytes. Following doses of 5 and 10 mg CCNU per kg b.wt. dominant lethals were induced in spermatids and spermatocytes similar to the results for higher doses of BCNU. Higher dose exposure to BCNU and CCNU was associated with dominant lethals expressed as pre-implantation loss (reduction in total number of implants). In addition, higher doses of CCNU showed a cytotoxic effect in differentiating spermatogonia. Both compounds induced specific-locus mutations in post-spermatogonial germ cell stages of mice. However, CCNU increased also the specific-locus mutation frequency in spermatogonia in two out of three experiments. We conclude in analogy with criteria developed by IARC, that BCNU and CCNU are potential human mutagens.
Asunto(s)
Antineoplásicos Alquilantes/toxicidad , Carmustina/toxicidad , Lomustina/toxicidad , Mutagénesis/efectos de los fármacos , Mutágenos/toxicidad , Animales , Femenino , Genes Dominantes/efectos de los fármacos , Genes Letales/efectos de los fármacos , Masculino , Ratones , Mutagénesis/genética , Pruebas de Mutagenicidad , Embarazo , Espermatozoides/efectos de los fármacosRESUMEN
Cat4 is the second largest allelism group in the collection of mouse dominant eye mutations recovered in Neuherberg and carriers express anterior polar cataract, central corneal opacity, and lens-corneal adhesions. We have mapped the Cat4 locus of the mouse to central Chromosome (Chr) 8 at position cM 31. Histological characterization of Cat4(a) heterozygotes and homozygotes indicates failure of separation of the lens vesicle from the surface ectoderm. Human anterior segment ocular dysgenesis (ASOD) is autosomal dominant, carriers express an eye phenotype similar to that of Cat4(a) carriers, and it has been mapped to a region of 4q homologous to mouse central Chr 8. Thus, on the basis of phenotype and map position, Cat4 may be a mouse model of human ASOD. The genes Junb, Jund1, Mel, and Zfp42 are discussed as possible candidates for Cat4.
Asunto(s)
Mapeo Cromosómico , Córnea/patología , Enfermedades de la Córnea/genética , Anomalías del Ojo/genética , Mutación , Animales , Segmento Anterior del Ojo/anomalías , Segmento Anterior del Ojo/patología , Córnea/efectos de la radiación , Opacidad de la Córnea/genética , Cruzamientos Genéticos , Ojo/patología , Rayos gamma , Ligamiento Genético , Marcadores Genéticos , Heterocigoto , Homocigoto , Humanos , Enfermedades del Cristalino/genética , Cristalino/patología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Mutantes , Adherencias Tisulares/genéticaRESUMEN
The Tcm mutation in the mouse is an autosomal dominant ocular malformation manifesting as microphthalmia, iris dysplasia, cataract, and coloboma. As a first step to cloning the Tcm gene, we report the localization of the Tcm mutation with respect to known microsatellite markers. Backcross progeny carrying the Tcm mutation were produced by mating Tcm/+ heterozygous mice to normal C57BL/6 partners. Genomic DNA from each mouse was subjected to PCR analysis to identify simple sequence length polymorphisms. Our results locate Tcm to Chr 4 and suggest candidate genes responsible for the Tcm phenotype. Finally, ocular histopathology was done in 3-week-old animals to define the extent of the malformation.
Asunto(s)
Mapeo Cromosómico , Anomalías del Ojo/genética , Anomalías Múltiples/genética , Animales , Anomalías del Ojo/patología , Femenino , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Polimorfismo GenéticoRESUMEN
Our earlier analyses have suggested an apparent threshold dose-response for ethylnitrosourea-induced specific-locus mutations in treated spermatogonia of the mouse to be due to a saturable repair process. In the current study a series of fractionated-treatment experiments was carried out in which male (102 x C3H)F1 mice were exposed to 4 x 10, 2 x 40. 4 x 20 or 4 x 40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4 x 40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2 x 40, 4 x 20 and 4 x 40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous specific-locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.
Asunto(s)
Etilnitrosourea/toxicidad , Mutágenos/toxicidad , Mutación , Espermatogonias/efectos de los fármacos , Animales , Etilnitrosourea/administración & dosificación , Femenino , Marcadores Genéticos , Infertilidad Masculina/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos , Pruebas de Mutagenicidad , Mutágenos/administración & dosificación , Fenotipo , Espermatogénesis/efectos de los fármacos , Factores de TiempoAsunto(s)
Elementos Transponibles de ADN , Mutación Puntual , Factor de Células Madre/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Tamización de Portadores Genéticos , Genotipo , Homocigoto , Ratones , Ratones Endogámicos C3H , Ratones Mutantes , Datos de Secuencia Molecular , Muridae , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Factor de Células Madre/biosíntesis , Factor de Células Madre/químicaRESUMEN
We describe a new mouse frameshift mutation (Pax2(1Neu)) with a 1-bp insertion in the Pax2 gene. This mutation is identical to a previously described mutation in a human family with renal-coloboma syndrome [Sanyanusin, P., McNoe, L. A., Sullivan, M. J., Weaver, R. G. & Eccles, M. R. (1995) Hum. Mol. Genet. 4, 2183-2184]. Heterozygous mutant mice exhibit defects in the kidney, the optic nerve, and retinal layer of the eye, and in homozygous mutant embryos, development of the optic nerve, metanephric kidney, and ventral regions of the inner ear is severely affected. In addition, we observe a deletion of the cerebellum and the posterior mesencephalon in homozygous mutant embryos demonstrating that, in contrast to mutations in Pax5, which is also expressed early in the mid-hindbrain region, loss of Pax2 gene function alone results in the early loss of the mid-hindbrain region. The mid-hindbrain phenotype is similar to Wnt1 and En1 mutant phenotypes, suggesting the conservation of gene regulatory networks between vertebrates and Drosophila.
Asunto(s)
Anomalías Múltiples/genética , Coloboma/genética , Proteínas de Unión al ADN/genética , Desarrollo Embrionario y Fetal , Mutación del Sistema de Lectura , Riñón/anomalías , Factores de Transcripción/genética , Animales , Secuencia de Bases , Encéfalo/anomalías , Cruzamientos Genéticos , Cartilla de ADN , Oído/anomalías , Anomalías del Ojo/genética , Homocigoto , Humanos , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Factor de Transcripción PAX2 , Fenotipo , Reacción en Cadena de la Polimerasa , Recombinación Genética , SíndromeRESUMEN
n-Propyl methanesulfonate (nPMS) and isopropyl methanesulfonate (iPMS) induce dominant lethal and specific-locus mutations in male mice. The response of the various spermatogenic stages to the induction of mutations differ markedly for nPMS and iPMS. Independent of the effective dose range the induction of dominant lethal mutations by nPMS is limited to spermatozoa and spermatids. In contrast, the induction of dominant lethal mutations by nPMS is limited to spermatozoa and spermatids. In contrast, the induction of dominant lethal mutations by iPMS is dose dependent: a dose of 20 mg iPMS/kg body weight (bw) is active only in spermatocytes, while a dose of 100 mg/kg bw induces dominant lethal mutations in all postspermatogonial germ cell stages. One other striking difference in the biological effectiveness of both compounds is that iPMS induces a sterile phase in stem-cell spermatogonia, whereas nPMS treated males even at the highest dose are fully fertile.
Asunto(s)
Alquilantes/toxicidad , Mesilatos/toxicidad , Mutagénesis Sitio-Dirigida , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Femenino , Genes Dominantes , Genes Letales , Infertilidad Masculina/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C3HRESUMEN
Inhalation exposure of mice to 50, 200, 500 or 1300 ppm of 1,3-butadiene for 6 h per day for 5 consecutive days caused micronuclei in mouse bone marrow and peripheral blood erythrocytes. The dose response was non-linear. The slope of the curve flattened with increasing exposure concentration. Coat color spots were found in the mouse spot test after exposure of pregnant females on pregnancy days 8-12 to 500 ppm of 1,3-butadiene. Dominant lethal mutations were induced in spermatozoa and late spermatids after exposure of male mice to 1300 ppm with the 5-day exposure regimen. Thus, in the mouse 1,3-butadiene is a somatic and germ cell mutagen.
Asunto(s)
Médula Ósea/efectos de los fármacos , Butadienos/toxicidad , Eritrocitos/efectos de los fármacos , Genes Dominantes , Genes Letales , Células Germinativas/efectos de los fármacos , Mutágenos/toxicidad , Preñez/efectos de los fármacos , Administración por Inhalación , Animales , Médula Ósea/patología , Células de la Médula Ósea , Butadienos/administración & dosificación , Cruzamientos Genéticos , Relación Dosis-Respuesta a Droga , Eritrocitos/citología , Eritrocitos/patología , Femenino , Citometría de Flujo , Color del Cabello , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos , Pruebas de Micronúcleos , Embarazo , Factores SexualesRESUMEN
We have compiled the reverse mutation rate data to the white bellied agouti (Aw) allele in heterozygous A/a mice and shown it to be increased by a factor of at least 350 in comparison to the reverse mutation rate in homozygous a/a mice. Employing tightly linked flanking restriction fragment length polymorphism DNA markers, we have shown that reversion to Aw is associated with crossing over in the vicinity of the agouti locus. The non-agouti (a) allele has been recently shown to contain an 11-kb insert within the first intron of the agouti gene. Together with our present results, these observations suggest possible mechanisms to explain the reversion events.