Heightened susceptibility to chronic gastritis, hyperplasia and metaplasia in Kcnq1 mutant mice.

Increased susceptibility to gastric cancer has been associated with a wide range of host genetic and environmental factors, including Helicobacter pylori infection. Helicobacter pylori infection is postulated to initiate a progression through atrophic gastritis, metaplasia and dysplasia to cancer, and has been associated with reduction of acid output and dysregulation of stomach mucins. Here, we present the characterization of two mouse lines carrying mutant alleles of the gene encoding the Kcnq1 potassium channel, which very rapidly establish chronic gastritis in a pathogen-exposed environment.

A chromosomal translocation causing multiple abnormalities including open eyelids at birth and glomerulonephritis.

We have characterized the phenotype of a mouse with a t(2;13) reciprocal translocation induced by chlorambucil. It results in abnormal eyelid formation as well as a series of neurological, physiological, and immunological abnormalities. This mutant has been termed T(2;13)1Fla/+.

A new mouse model for autosomal recessive polycystic kidney disease.

In the course of large-scale mutagenesis studies, we discovered a mutant that provides a new mouse model for human autosomal recessive polycystic kidney disease. Animals homozygous for this mutation, T(2;10)67Gso, present evidence of grossly cystic renal and hepatic tissue at birth and a limited survival time of 3-4 days. The recessively expressed phenotype is associated with inheritance of a reciprocal translocation involving mouse chromosomes 2 and 10.

A new mouse insertional mutation that causes sensorineural deafness and vestibular defects.

This article describes a new recessive insertional mutation in the transgenic line TgN2742Rpw that causes deafness and circling behavior in mice. Histologic analysis revealed virtually complete loss of the cochlear neuroepithelium (the organ of Corti) in adult mutant mice. In association with the neuroepithelial changes, there is a dramatic reduction of the cochlear nerve supply.

Generation and characterization of heritable reciprocal translocations in mice.

Reciprocal translocations have provided crucial tools for the localization of genes associated with a variety of human cancers and hereditary diseases. Although heritable translocations are relatively rare in humans, they can be easily induced in mice through exposure of male germ cells at specific spermatogenic stages to different types of radiation and chemicals. Mutagenesis schemes that produce translocations at high frequencies in the progeny of treated males are summarized, and the use of these valuable mutations for analyzing developmental consequences of partial aneuploidy, for identification of mutant genes, and for other purposes is reviewed.

Induced mouse chromosomal rearrangements as tools for identifying critical developmental genes and pathways.

Due to the rapid advances that have been made in molecular and genetic technology during the past decade, the genes associated with a large number of human hereditary diseases have been isolated and analyzed in detail. These cloned genes provide new tools for research geared toward a better understanding of normal human development, and also of the many ways that basic, essential morphologic pathways can be disturbed. Chromosomal rearrangements, especially deletions and translocations, have been especially beneficial in the mapping and isolation of human disease genes because of their visibility on both the cytogenetic and molecular levels.

Dominant lethal mutations, heritable translocations, and unscheduled DNA synthesis induced in male mouse germ cells by glycidamide, a metabolite of acrylamide.

The hypothesis that acrylamide induces dominant lethal mutations and heritable translocations in male mice, not through direct adduction, but by conversion to the reactive epoxide, glycidamide, was investigated. Three studies, namely, induction of dominant lethal mutations, heritable translocations, and unscheduled DNA synthesis in spermatids, which were conducted earlier in this laboratory for acrylamide, were also performed for glycidamide to determine its mutagenic properties and to compare responses. Results of these studies are consistent with the proposal that in vivo conversion to glycidamide is responsible for the mutagenicity of acrylamide in male mice.

Complementation analyses for 45 mutations encompassing the pink-eyed dilution (p) locus of the mouse.

The homozygous and heterozygous phenotypes are described and characterized for 45 new pink-eyed dilution (p) locus mutations, most of them radiation-induced, that affect survival at various stages of mouse development. Cytogenetically detectable aberrations were found in three of the new p mutations (large deletion, inversion, translocation), with band 7C involved in each case. The complementation map developed from the study of 810 types of compound heterozygotes identifies five functional units: jls and jlm (two distinct juvenile-fitness functions, the latter associated with neuromuscular defects), pl-1 and pl-2 (associated with early-postimplantation and preimplantation death, respectively), and nl [neonatal lethality associated with cleft palate (the frequency of rare "escapers" from this defect varied with the genotype)].

Dominant lethal and heritable translocation tests with chlorambucil and melphalan in male mice.

Chemicals used in the treatment of cancer include several that are potent mutagens in a range of in vitro and in vivo assays. For some, genetic effects have also been demonstrated in humans, detected as chromosomal aberrations in peripheral lymphocytes. Because (1) many of these agents are confirmed mutagens, (2) humans are exposed to them in relatively high doses, and (3) an increasing number of early cancer victims are surviving to reproductive age, it is important that information be available on the genetic and reproductive hazards associated with exposure to these agents.

Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice.

A line of transgenic mice was generated that contains an insertional mutation causing a phenotype similar to human autosomal recessive polycystic kidney disease. Homozygotes displayed a complex phenotype that included bilateral polycystic kidneys and an unusual liver lesion. The mutant locus was cloned and characterized through use of the transgene as a molecular marker.

Cytogenetic analysis of malformed mouse fetuses derived from balanced translocation heterozygotes.

Reciprocal translocations are readily induced by various physical and chemical mutagens in certain germ-cell stages. Carriers of balanced reciprocal translocations generally exhibit no abnormal phenotypes, except for occasional male sterility, but about half (on average) of their progeny carry grossly unbalanced chromosome complements and die prenatally, so that the carriers are said to be 'semisterile'. Since death of such progeny generally occurs in very early embryonic stages, it would be of minor importance in an analogous human situation.

Molecular characterization of a pericentric inversion in mouse chromosome 8 implicates telomeres as promoters of meiotic recombination.

A "hot spot" of meiotic recombination has been found in males on murine chromosome 8 using nonisotopic hybridization of a series of probes to mitotic and meiotic chromosomes. The sequences responsible for this enhanced recombination are the telomeric repeats. Mice both normal and hetero- or homozygous for a pericentric inversion, In(8)1 Rl, were analyzed.

Genetic, cytogenetic, and molecular analyses of mutations induced by melphalan demonstrate high frequencies of heritable deletions and other rearrangements from exposure of postspermatogonial stages of the mouse.

Specific-locus experiments have previously shown melphalan to be mutagenic in all male germ-cell stages tested and particularly so in early spermatids. All but 2 of 24 specific-locus mutations recovered were tested genetically, cytogenetically, and/or molecularly. At least 12 of 15 tested mutations recovered from postspermatogonial stages but only 1 of 7 mutations recovered from stem-cell or differentiating spermatogonia gave evidence of being deletions or other rearrangements.

Induction of specific-locus mutations in male germ cells of the mouse by acrylamide monomer.

Acrylamide monomer (AA), injected into male mice at the maximum tolerated dose of 5 x 50 mg/kg (24-h intervals), significantly increased the specific-locus mutation rate in certain poststem-cell stages of spermatogenesis, but not in spermatogonial stem cells. Germ-cell stages in which the treatment induced dominant lethals--namely, exposed spermatozoa and late spermatids (number of surviving offspring only 3% and 27%, respectively, of those in concurrent controls)--jointly yielded the highest frequency of specific-locus mutations. AA thus conforms to Pattern 1 in our earlier classification of chemicals according to the spermatogenic stage at which they elicit maximum response (Russell et al.

Molecular and genetic characterization of a radiation-induced structural rearrangement in mouse chromosome 2 causing mutations at the limb deformity and agouti loci.

Molecular characterization of mutations in the mouse, particularly those involving agent-induced major structural alterations, is proving to be useful for correlating the structure and expression of individual genes with their function in the whole organism. Here we present the characterization of a radiation-induced mutation that simultaneously generated distinct alleles of both the limb deformity (ld) and agouti (a) loci, two developmentally important regions of chromosome 2 normally separated by 20 centimorgans. Cytogenetic analysis revealed that an interstitial segment of chromosome 17 (17B- 17C; or, possibly, 17A2-17B) had been translocated into the distal end of chromosome 2, resulting in a smaller-than-normal chromosome 17 (designated 17del) and a larger form of chromosome 2 (designated 2(17).

Increased incidence of developmental anomalies among descendants of carriers of methylenebisacrylamide-induced balanced reciprocal translocations.

N,N'-Methylenebisacrylamide (MBA), a dimer of the monomeric acrylamide, was studied for induction of clastogenic effects in germ cells of male mice. It was found to be effective in inducing dominant-lethal mutations and heritable translocations in maturing sperm. The semisterile translocation carriers and their normal counterparts were used to determine the health impact of transmitted chromosomal rearrangements through anatomical analysis of their immediate descendants in utero.

Genetic and molecular analysis of chlorambucil-induced germ-line mutations in the mouse.

Eighteen variants recovered from specific locus mutation rate experiments involving the mutagen chlorambucil were subjected to several genetic and molecular analyses. Most mutations were found to be homozygous lethal. Because lethality is often presumptive evidence for multilocus-deletion events, 10 mutations were analyzed by Southern blot analysis with probes at, or closely linked to, several of the specific locus test markers, namely, albino (c), brown (b), and dilute (d).

Concentration-response curves for ethylene-oxide-induced heritable translocations and dominant lethal mutations.

Male mice were subjected to repeated inhalation exposures to different concentrations (165, 204, 250, or 300 ppm) of ethylene oxide (EtO) during an 8.5-week period. Transmitted clastogenic effects of these exposures were measured in terms of induction of dominant lethal mutations and heritable translocations.

Correlation between meiotic behavior and breakpoints with respect to G-bands in two X-4 mouse translocations: T(X;4)7R1 and T(X;4)8R1.

The meiotic synaptic behavior of male mice heterozygous for one of two X-4 translocations was examined to test a recently advanced hypothesis (Ashley, 1988) suggesting that it is possible to predict the synaptic behavior (nonhomologous vs. homologous) and recombinational parameters (suppression vs. nonsuppression of crossing-over) of a chromosome aberration from mitotic G-band breakpoint data.

Chlorambucil effectively induces deletion mutations in mouse germ cells.

The chemotherapeutic agent chlorambucil was found to be more effective than x-rays or any chemical investigated to date in inducing high yields of mouse germ-line mutations that appear to be deletions or other structural changes. Induction of mutations involving seven specific loci was studied after exposures of various male germ-cell stages to chlorambucil at 10-25 mg/kg. A total of 60,750 offspring was scored.

Fetal anomalies produced subsequent to treatment of zygotes with ethylene oxide or ethyl methanesulfonate are not likely due to the usual genetic causes.

Earlier studies in this laboratory revealed that ethylene oxide (EtO) or ethyl methanesulfonate (EMS) induced high frequencies of midgestation and late fetal deaths, and of malformations among some of the surviving fetuses, when female mice were exposed at the time of fertilization of their eggs or during the early pronuclear stage of the zygote. Effects of the two mutagens are virtually identical. Thus, in investigating the mechanisms responsible for the dramatic effects in the early pronuclear zygotes, the two compounds were used interchangeably in the experiments.

No evidence found for induction of dominant lethal mutations and heritable translocations in male mice by calcium cyclamate.

Calcium cyclamate, an artificial sweetener, was studied for its effectiveness in inducing transmissible chromosomal aberrations in germ cells of male mice. Both the dominant-lethal and the heritable translocation tests were carried out following daily treatment (on weekdays) of males by oral intubation with the maximum tolerated dose for 6 weeks. Calcium cyclamate is negative in both tests; therefore, there is no evidence of induced chromosome breakage and exchange.

Mouse specific-locus test for the induction of heritable gene mutations by dibromochloropropane (DBCP).

The nematocide DBCP (1,2-dibromo-3-chloropropane) produced negative results in a specific-locus test for gene-mutation induction in the germline of male (101 X C3H)F1 mice, most of which were treated with 5 daily intraperitoneal injections of 80 mg/kg (total exposure, 400 mg/kg); a few received lower exposures. For treated spermatogonial stem cells, the finding of 2 mutations among 39519 offspring--a rate almost identical to the control rate--rules out (at the 5% significance level) an induced mutation frequency greater than 2.0 times the historical control rate.

A balanced translocation in mice with a neurological defect.

A semisterile male translocation heterozygote [t(2; 14) 1Gso] that exhibited neurological symptoms and an inability to swim (diver) was found among the offspring of male mice treated with triethylenemelamine. All breeding and cytogenetic data showed a complete concordance between translocation heterozygosity and the neurological disorders. Homozygosity for the translocation seemed to be lethal at an early embryonic stage.