RESUMEN
Paenibacillus larvae bacteriophage Tripp was isolated from an American foulbrood diseased honey bee hive in North Carolina, USA. The 54,439-bp genome is 48.3% G+C, encodes 92 proteins, no tRNAs, and has 378-bp direct terminal repeats. It is currently unique in Genbank.
RESUMEN
We report the chromosomal localization, mutant gene identification, ophthalmic appearance, histology, and functional analysis of two new hereditary mouse models of retinal degeneration not having the Pde6brd1("r", "rd", or "rodless") mutation. One strain harbors an autosomal recessive mutation that maps to mouse chromosome 5. Sequence analysis showed that the retinal degeneration is caused by a missense point mutation in exon 13 of the beta-subunit of the rod cGMP phosphodiesterase (beta-PDE) gene (Pde6b). The gene symbol for this strain was set as Pde6brd10, abbreviated rd10 hereafter. Mice homozygous for the rd10 mutation showed histological changes at postnatal day 16 (P16) of age and sclerotic retinal vessels at four weeks of age, consistent with retinal degeneration. Retinal sections were highly positive for TUNEL and activated caspase-3 immunoreactivity, specifically in the outer nuclear layer (ONL). ERGs were never normal, but rod and cone ERG a- and b-waves were easily measured at P18 and steadily declined over 90% by two months of age. Protein extracts from rd10 retinas were positive for beta-PDE immunoreactivity starting at about the same time as wild-type (P10), though signal averaged less than 40% of wild-type. Interestingly, rearing rd10 mice in total darkness delayed degeneration for at least a week, after which morphological and functional loss progressed irregularly. With the second strain, a complementation test with rd1 mice revealed that the retinal degeneration phenotype observed represents a possible new allele of Pde6b. Sequencing demonstrated a missense point mutation in exon 16 of the beta-subunit of rod phosphodiesterase gene, different from the point mutations in rd1 and rd10. The gene symbol for this strain was set as Pde6bnmf137, abbreviated nmf137 hereafter. Mice homozygous for this mutation showed retinal degeneration with a mottled retina and white retinal vessels at three weeks of age. The exon 13 missense mutation (rd10) is the first known occurrence of a second mutant allele spontaneously arising in the Pde6b gene in mice and may provide a model for studying the pathogenesis of autosomal recessive retinitis pigmentosa (arRP) in humans. It may also provide a better model for experimental pharmaceutical-based therapy for RP because of its later onset and milder retinal degeneration than rd1 and nmf137.
Asunto(s)
Mutación Missense , Hidrolasas Diéster Fosfóricas/genética , Degeneración Retiniana/genética , Células Fotorreceptoras Retinianas Bastones/enzimología , Animales , Apoptosis , Secuencia de Bases , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6 , Adaptación a la Oscuridad , Modelos Animales de Enfermedad , Electrorretinografía , Proteínas del Ojo/genética , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Fenotipo , Hidrolasas Diéster Fosfóricas/metabolismo , Degeneración Retiniana/enzimología , Degeneración Retiniana/patologíaRESUMEN
The Jackson Laboratory, having the world's largest collection of mouse mutant stocks and genetically diverse inbred strains, is an ideal place to discover genetically determined eye variations and disorders. In this paper, we list and describe mouse models for ocular research available from Mouse Eye Mutant Resource at The Jackson Laboratory. While screening mouse strains and stocks at The Jackson Laboratory (TJL) for genetic mouse models of human ocular disorders, we have identified numerous spontaneous or naturally occurring mutants. We characterized these mutants using serial indirect ophthalmoscopy, fundus photography, electroretinography (ERG) and histology, and performed genetic analysis including linkage studies and gene identification. Utilizing ophthalmoscopy, electroretinography, and histology, to date we have discovered 109 new disorders affecting all aspects of the eye including the lid, cornea, iris, lens, and retina, resulting in corneal disorders, glaucoma, cataracts, and retinal degenerations. The number of known serious or disabling eye diseases in humans is large and affects millions of people each year. Yet research on these diseases frequently is limited by the obvious restrictions on studying pathophysiologic processes in the human eye. Likewise, many human ocular diseases are genetic in origin, but appropriate families often are not readily available for genetic studies. Mouse models of inherited ocular disease provide powerful tools for rapid genetic analysis, characterization, and gene identification. Because of the great similarity among mammalian genomes, these findings in mice have direct relevance to the homologous human conditions.
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Oftalmopatías/genética , Ratones Mutantes/genética , Animales , Catarata/genética , Catarata/patología , Cromosomas/metabolismo , Cromosomas/ultraestructura , Modelos Animales de Enfermedad , Electrorretinografía , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Oftalmopatías/patología , Oftalmopatías/fisiopatología , Glaucoma/genética , Glaucoma/patología , Ratones , Oftalmoscopía , Enfermedades de la Retina/genética , Enfermedades de la Retina/patologíaRESUMEN
The Jackson Laboratory, having the world's largest collection of mouse mutant stocks and genetically diverse inbred strains, is an ideal place to look for genetically determined eye variations and disorders. Through ophthalmoscopy, electroretinography and histology, we have discovered disorders affecting all aspects of the eye including the lid, cornea, iris, lens and retina, resulting in corneal disorders, cataracts, glaucoma and retinal degenerations. Mouse models of retinal degeneration have been investigated for many years in the hope of understanding the causes of photoreceptor cell death. Sixteen naturally occurring mouse mutants that manifest degeneration of photoreceptors in the retina with preservation of all other retinal cell types have been found: retinal degeneration (formerly rd, identical with rodless retina, r, now Pde6b(rd1)); Purkinje cell degeneration (pcd); nervous (nr); retinal degeneration slow (rds, now Prph(Rd2)); retinal degeneration 3 (rd3); motor neuron degeneration (mnd); retinal degeneration 4 (Rd4); retinal degeneration 5 (rd5, now tub); vitiligo (vit, now Mitf(mi-vit)); retinal degeneration 6 (rd6); retinal degeneration 7 (rd7, now Nr2e3(rd7)); neuronal ceroid lipofuscinosis (nclf); retinal degeneration 8 (rd8); retinal degeneration 9 (Rd9); retinal degeneration 10 (rd10, now Pde6b(rd10)); and cone photoreceptor function loss (cpfl1). In this report, we first review the genotypes and phenotypes of these mutants and second, list the mouse strains that carry each mutation. We will also provide detailed information about the cpfl1 mutation. The phenotypic characteristics of cpfl1 mice are similar to those observed in patients with complete achromatopsia (ACHM2, OMIM 216900) and the cpfl1 mutation is the first naturally-arising mutation in mice to cause cone-specific photoreceptor function loss. cpfl1 mice may provide a model for congenital achromatopsia in humans.
Asunto(s)
Apoptosis , Ratones Mutantes , Modelos Animales , Células Fotorreceptoras de Vertebrados/patología , Degeneración Retiniana/genética , Animales , Electrorretinografía , Fondo de Ojo , Ratones , Retina/metabolismo , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Rodopsina/metabolismoRESUMEN
BACKGROUND: Glaucoma is a blinding disease usually associated with high intraocular pressure (IOP). In some families, abnormal anterior segment development contributes to glaucoma. The genes causing anterior segment dysgenesis and glaucoma in most of these families are not identified and the affected developmental processes are poorly understood. Bone morphogenetic proteins (BMPs) participate in various developmental processes. We tested the importance of Bmp4 gene dosage for ocular development and developmental glaucoma. RESULTS: Bmp4+/- mice have anterior segment abnormalities including malformed, absent or blocked trabecular meshwork and Schlemm's canal drainage structures. Mice with severe drainage structure abnormalities, over 80% or more of their angle's extent, have elevated IOP. The penetrance and severity of abnormalities is strongly influenced by genetic background, being most severe on the C57BL/6J background and absent on some other backgrounds. On the C57BL/6J background there is also persistence of the hyaloid vasculature, diminished numbers of inner retinal cells, and absence of the optic nerve. CONCLUSIONS: We demonstrate that heterozygous deficiency of BMP4 results in anterior segment dysgenesis and elevated IOP. The abnormalities are similar to those in human patients with developmental glaucoma. Thus, BMP4 is a strong candidate to contribute to Axenfeld-Rieger anomaly and other developmental conditions associated with human glaucoma. BMP4 also participates in posterior segment development and wild-type levels are usually critical for optic nerve development on the C57BL/6J background. Bmp4+/- mice are useful for studying various components of ocular development, and may allow identification of strain specific modifiers affecting a variety of ocular phenotypes.
Asunto(s)
Segmento Anterior del Ojo/crecimiento & desarrollo , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/fisiología , Presión Intraocular , Hipertensión Ocular/etiología , Animales , Segmento Anterior del Ojo/anomalías , Proteína Morfogenética Ósea 4 , Electrorretinografía , Anomalías del Ojo/etiología , Anomalías del Ojo/patología , Dosificación de Gen , Heterocigoto , Ratones , Ratones Endogámicos C57BL , Hipertensión Ocular/patología , Nervio Óptico/crecimiento & desarrollo , Fenotipo , Vasos Retinianos/crecimiento & desarrolloRESUMEN
The paracentric inversion In(3)55Rk on mouse Chromosome 3 (Chr 3) was induced by cesium irradiation. Genetic crosses indicate the proximal breakpoint cosegregates with D3Mit324 and D3Mit92; the distal breakpoint cosegregates with D3Mit127, D3Mit160, and D3Mit200. Giemsa-banded chromosomes show the inversion spans approximately 80% of Chr 3. The proximal breakpoint occurs within band 3A2, not 3B as reported previously; the distal breakpoint occurs within band 3H3. Mice homozygous for the inversion exhibit nephropathy indicative of uricase deficiency. Southern blot analyses of urate oxidase, Uox, show two RFLPs of genomic mutant DNA: an EcoRI site between exons 4-8 and a BamHI site 3' to exon 6. Mutant cDNA fails to amplify downstream of base 844 at the 3' end of exon 7. FISH analysis of chromosomes from inversion heterozygotes, using a cosmid clone containing genomic wild-type DNA for Uox exons 2-4, shows that a 5' segment of the mutated Uox allele on the inverted chromosome has been transposed from the distal breakpoint region to the proximal breakpoint region. Clinical, histopathological, and Northern analyses indicate that our radiation-induced mutation, uox(In), is a putative null.
Asunto(s)
Inversión Cromosómica , Enfermedades Renales/genética , Mutación/genética , Urato Oxidasa/genética , Alelos , Animales , Southern Blotting , Bandeo Cromosómico , Mapeo Cromosómico , Cruzamientos Genéticos , Análisis Mutacional de ADN , Exones/genética , Femenino , Hibridación Fluorescente in Situ , Enfermedades Renales/enzimología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Masculino , Ratones , Ratones Mutantes , Polimorfismo de Longitud del Fragmento de Restricción , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ácido Úrico/sangre , Ácido Úrico/metabolismoRESUMEN
BACKGROUND: Glaucoma is a common disease but its molecular etiology is poorly understood. It involves retinal ganglion cell death and optic nerve damage that is often associated with elevated intraocular pressure. Identifying genes that modify glaucoma associated phenotypes is likely to provide insights to mechanisms of glaucoma. We previously reported glaucoma in DBA/2J mice caused by recessive alleles at two loci, isa and ipd, that cause iris stromal atrophy and iris pigment dispersion, respectively. A approach for identifying modifier genes is to study the effects of specific mutations in different mouse strains. When the phenotypic effect of a mutation is modified upon its introduction into a new strain, crosses between the parental strains can be used to identify modifier genes. The purpose of this study was to determine if the effects of the DBA/2J derived isa and ipd loci are modified in strain AKXD-28/Ty. RESULTS: AKXD-28/Ty mice develop glaucoma characterized by intraocular pressure elevation, retinal ganglion loss, and optic nerve excavation. In AKXD-28/Ty, isa causes an iris stromal atrophy phenotype as in DBA/2J. However, the iris pigment dispersion phenotype associated with ipd in DBA/2J does not occur in AKXD-28/Ty. Additionally, a greater severity and speed of retinal and optic nerve damage following intraocular pressure elevation in AKXD-28/Ty compared to DBA/2J mice suggests that AKXD-28/Ty is more susceptible to pressure-induced cell death. CONCLUSIONS: The consequences of the ipd and isa mutations are modified in the AKXD-28/Ty background. These strains provide a resource for the identification of modifier genes that modulate pigment dispersion and susceptibility to pressure-induced cell death.
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Predisposición Genética a la Enfermedad , Glaucoma/genética , Glaucoma/patología , Animales , Atrofia , Femenino , Glaucoma/diagnóstico , Iris/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos , Mutación , Enfermedades del Nervio Óptico/genética , Enfermedades del Nervio Óptico/patología , Fenotipo , Epitelio Pigmentado Ocular/patología , Enfermedades de la Retina/genética , Enfermedades de la Retina/patología , Factores Sexuales , Especificidad de la EspecieRESUMEN
PURPOSE: To characterize the genetics and phenotype of a new mouse mutant with retinal degeneration, rd6, that is associated with extensive, scattered, small white retinal dots seen ophthalmoscopically. METHODS: The phenotype was characterized using ophthalmoscopy, fundus photography, electroretinography, light microscopy, immunocytochemistry, and electron microscopy. Genetic characterization and linkage analysis studies were performed using standard methods. RESULTS: The inheritance pattern of rd6 is autosomal recessive. Linkage analysis mapped rd6 to mouse Chromosome 9 approximately 24 cM from the centromere, suggesting that the human homolog may be on chromosome 11q23. Ophthalmoscopic examination of mice homozygous for rd6 revealed discrete subretinal spots oriented in a regular pattern across the retina. The retinal spots appeared by 8 to 10 weeks of age and persisted through advanced stages of retinal degeneration. Histologic examination revealed large cells in the subretinal space, typically juxtaposed to the retinal pigment epithelium. The white dots seen on fundus examination corresponded both in distribution and size to these large cells. By 3 months of age, the cells were filled with membranous profiles, lipofuscin-like material, and pigment. These cells reacted strongly with an antibody directed against a mouse macrophage-associated antigen. Photoreceptor cells progressively degenerated with age, and an abnormal electroretinogram was initially detected between 1 and 2 months of age. CONCLUSIONS: The fundi of mice homozygous for rd6 exhibit phenotypic similarities to the human flecked retinal disorder retinitis punctata albescens. Thus, rd6/rd6 mice may be a model for understanding the etiology of this or similar disorders. The relationship between the aberrant subretinal cells and the concomitant photoreceptor degeneration remains to be established.
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Modelos Animales de Enfermedad , Ceguera Nocturna/genética , Células Fotorreceptoras de Vertebrados/ultraestructura , Degeneración Retiniana/genética , Animales , Mapeo Cromosómico , Cromosomas/genética , Electrorretinografía , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Ligamiento Genético , Masculino , Ratones , Ratones Endogámicos C3H , Ceguera Nocturna/fisiopatología , Oftalmoscopía , Fenotipo , Células Fotorreceptoras de Vertebrados/fisiología , Degeneración Retiniana/patología , Degeneración Retiniana/fisiopatologíaRESUMEN
The rd7 mouse, an animal model for hereditary retinal degeneration, has some characteristics similar to human flecked retinal disorders. Here we report the identification of a deletion in a photoreceptor-specific nuclear receptor (mPNR) mRNA that is responsible for hereditary retinal dysplasia and degeneration in the rd7 mouse. mPNR was isolated from a pool of photoreceptor-specific cDNAs originally created by subtractive hybridization of mRNAs from normal and photoreceptorless rd mouse retinas. Localization of the gene corresponding to mPNR to mouse Chr 9 near the rd7 locus made it a candidate for the site of the rd7 mutation. Northern analysis of total RNA isolated from rd7 mouse retinas revealed no detectable signal after hybridization with the mPNR cDNA probe. However, with reverse transcription-PCR, we were able to amplify different fragments of mPNR from rd7 retinal RNA and to sequence them directly. We found a 380-nt deletion in the coding region of the rd7 mPNR message that creates a frame shift and produces a premature stop codon. This deletion accounts for more than 32% of the normal protein and eliminates a portion of the DNA-binding domain. In addition, it may result in the rapid degradation of the rd7 mPNR message by the nonsense-mediated decay pathway, preventing the synthesis of the corresponding protein. Our findings demonstrate that mPNR expression is critical for the normal development and function of the photoreceptor cells.
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Mapeo Cromosómico , Células Fotorreceptoras de Vertebrados/fisiología , ARN Mensajero/genética , Receptores Citoplasmáticos y Nucleares/genética , Degeneración Retiniana/genética , Factores de Transcripción , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Codón de Terminación , Cartilla de ADN , Electrorretinografía , Marcadores Genéticos , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Mutantes , Datos de Secuencia Molecular , Receptores Nucleares Huérfanos , Células Fotorreceptoras de Vertebrados/patología , Degeneración Retiniana/patología , Degeneración Retiniana/fisiopatología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Eliminación de SecuenciaRESUMEN
A new cataract mutation was discovered in an ongoing program to identify new mouse models of hereditary eye disease. Lens opacity 12 (Lop12) is a semidominant mutation that results in an irregular nuclear lens opacity similar to the human Coppock cataract. Lop12 is associated with a small nonrecombining segment that maps to mouse Chromosome 1 close to the eye lens obsolescence mutation (Cryge(Cat2-Elo)), a member of the gamma-crystallin gene cluster (Cryg). Using a systemic candidate gene approach to analyze the entire Cryg cluster, a G to A transition was found in exon 3 of Crygd associated with the Lop12 mutation and has been designated Crygd(Lop12). The mutation Crygd(Lop12) leads to the formation of an in-frame stop codon that produces a truncated protein of 156 amino acids. It is predicted that the defective gene product alters protein folding of the gamma-crystallin(s) and results in lens opacity.
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Catarata/genética , Cristalinas/genética , Modelos Animales de Enfermedad , Ratones/genética , Animales , Catarata/patología , Mapeo Cromosómico , Cruzamientos Genéticos , Cristalinas/química , Análisis Mutacional de ADN , ADN Complementario/genética , Femenino , Ligamiento Genético , Humanos , Masculino , Ratones Endogámicos BALB C , Pliegue de Proteína , Especificidad de la Especie , Regiones Terminadoras GenéticasRESUMEN
Ocular neovascularization is the leading cause of blindness in developed countries and often causes rapid loss of vision in age-related macular degeneration. Acute visual loss is most often due to hemorrhage from new vessels that have extended from the choroid into the subretinal space. Growth of abnormal vessels beneath the retina in this condition is known as subretinal neovascularization (SRN). Age-related animal models of macular degeneration and SRN have not been described. Current animal models of SRN depend on chemical or physical stimuli to initiate growth of subretinal vessels. The genes responsible for age-related human macular degeneration with SRN have not been firmly identified. We report an angiogenic phenotype in Bst/+ mice that is age-related, clinically evident, and resembles human SRN. This represents a spontaneous, genetically determined model of SRN. Bst/+ mice offer the possibility of exploring the molecular mechanisms of SRN without the need for exogenous agents.
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Envejecimiento/fisiología , Neovascularización Retiniana/genética , Animales , Mapeo Cromosómico , Modelos Animales de Enfermedad , Ojo/patología , Angiografía con Fluoresceína , Ratones , Ratones Endogámicos C57BL , Neovascularización Retiniana/patologíaRESUMEN
PURPOSE: The mouse lop18 (lens opacity 18) mutation causes a white cataract obvious at weaning age. It soon progresses to a large white nuclear cataract with mild cortical changes. The mutation maps to mouse Chromosome 17 in close linkage to the alphaA-crystallin (Crya) gene, which encodes one of the major vertebrate eye lens proteins. Here we report the identification of a missense mutation in the alphaA-crystallin gene of lop18/lop18 mutant mice. METHODS: PCR primers were designed based on the alphaA-crystallin gene sequence from GenBank and PCR products were sequenced. RESULTS: We have analysed the sequence of the alphaA-crystallin gene from the lop18/lop18 mouse and identified a missense mutation. This mutation is tightly associated with the cataract phenotype, as no recombination was detected in 112 meioses. CONCLUSIONS: Our results suggest that a missense mutation in the alphaA-crystallin gene is responsible for the lop18/lop18 phenotype and Cryalop18 should be used as a gene symbol for the lop18 mutation.
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Catarata/genética , Cristalinas/genética , Animales , Secuencia de Bases , Ratones , Ratones Endogámicos , Ratones Mutantes , Mutación Missense , Reacción en Cadena de la PolimerasaRESUMEN
PURPOSE: Mice are an increasingly important tool in ophthalmic research. As a result of studying spontaneous and induced mutations, many new ocular diseases have been described in mice in recent years, including several degenerative retinal diseases that demonstrate progression with age. Clearly, documentation of progressive changes in clinical phenotype is an important facet of characterizing new mutations and for comparing them with human diseases. Despite these facts, there are few published photographs of mouse fundi. The small size of the mouse eye and the steep curvature of its structures have made it difficult to obtain high quality fundus photographs. The purpose of this work was to develop procedures for mouse fundus photography and angiography and to use these techniques to examine several new mouse strains with ocular abnormalities. METHODS: We have used a small animal fundus camera and condensing lens to develop a reliable technique for producing high quality fundus images of conscious albino and pigmented mice. The fundus camera also was utilized to develop a method for fluorescein angiography, which demonstrated the normal retinal vascular bed as well as abnormal vascular leakage. In addition, several mouse strains with previously unreported ocular abnormalities (including two with inherited optic nerve colobomas) and a catalogue of previously unpublished clinical images for various mutant mice are presented. RESULTS: Altogether, we provide clinical images for C57BL/6J, BALB/cByJ, retinal degeneration 1 (rd1), Rd2, rd3, rd7, achondroplasia, nervous, motor neuron degeneration, Purkinje cell degeneration, kidney and retinal defects, optic nerve coloboma 1, and two apparently multigenic optic nerve colobomas in a strain of mixed derivation (ONC) and the inbred CALB/Rk strain. CONCLUSIONS: Our photography procedure reliably produces high quality images of the mouse fundus. This permitted us to record progressive retinal changes over time in the same animal, allowed us to compare the phenotypes of newly discovered retinal mutants to existing mutants at other institutions and to potentially similar human conditions, and finally, permitted us to produce a catalogue of previously unpublished clinical phenotypes for various mutant mice.
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Angiografía con Fluoresceína/métodos , Fondo de Ojo , Oftalmoscopios , Fotograbar/métodos , Vasos Retinianos/anatomía & histología , Animales , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones EndogámicosRESUMEN
PURPOSE: To demonstrate the importance of genetic background interaction on the development of ocular phenotypes in p53-deficient mice. METHODS: Eyes of adult mice, homozygous and heterozygous for the p53 gene disruption in the 129/SvJ and C57BL/6J (B6) genetic backgrounds, and their F1 progeny were examined by indirect ophthalmoscopy and by light microscopy. RESULTS: Indirect ophthalmoscopy revealed unilateral or bilateral vitreal opacities, fibrous retrolental tissue, and retinal folds in adult B6 mice but not in 129/Sv mice homozygous for a p53 null mutation. In B6 p53-/- mice, blood vessels extended from the peripapillary inner retina through the posterior vitreous and into the retrolental membrane. Optic nerves were hypoplastic. CONCLUSIONS: These findings indicate that alleles from the B6 background contribute to the aberrant ocular phenotypes observed in p53 deficiency. They also suggest that p53 or the pathway in which it functions may be important for normal eye development.
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Anomalías Múltiples/genética , Anomalías del Ojo/genética , Genes p53/genética , Retina/anomalías , Proteína p53 Supresora de Tumor/deficiencia , Cuerpo Vítreo/anomalías , Anomalías Múltiples/patología , Animales , Catarata/genética , Catarata/patología , Cartilla de ADN/química , Anomalías del Ojo/patología , Oftalmopatías/genética , Oftalmopatías/patología , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Nervio Óptico/anomalías , Nervio Óptico/patología , Fenotipo , Retina/patología , Displasia Retiniana/genética , Displasia Retiniana/patología , Proteína p53 Supresora de Tumor/genética , Cuerpo Vítreo/patologíaRESUMEN
Glaucomas are a major cause of blindness. Visual loss typically involves retinal ganglion cell death and optic nerve atrophy subsequent to a pathologic elevation of intraocular pressure (IOP). Some human glaucomas are associated with anterior segment abnormalities such as pigment dispersion syndrome (PDS) and iris atrophy with associated synechiae. The primary causes of these abnormalities are unknown, and their aetiology is poorly understood. We recently characterized a mouse strain (DBA/2J) that develops glaucoma subsequent to anterior segment changes including pigment dispersion and iris atrophy. Using crosses between mouse strains DBA/2J (D2) and C57BL/6J (B6), we now show there are two chromosomal regions that contribute to the anterior segment changes and glaucoma. Progeny homozygous for the D2 allele of one locus on chromosome 6 (called ipd) develop an iris pigment dispersion phenotype similar to human PDS. ipd resides on a region of mouse chromosome 6 with conserved synteny to a region of human chromosome 7q that is associated with human PDS. Progeny homozygous for the D2 allele of a different locus on chromosome 4 (called isa) develop an iris stromal atrophy phenotype (ISA). The Tyrpl gene is a candidate for isa and likely causes ISA via a mechanism involving pigment production. Progeny homozygous for the D2 alleles of both ipd and isa develop an earlier onset and more severe disease involving pigment dispersion and iris stromal atrophy.
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Glaucoma/genética , Enfermedades del Iris/genética , Iris/patología , Glicoproteínas de Membrana , Ratones Endogámicos DBA/genética , Oxidorreductasas , Factores de Edad , Animales , Atrofia , Mapeo Cromosómico , Cruzamientos Genéticos , Homocigoto , Enfermedades del Iris/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos , Repeticiones de Microsatélite , Epitelio Pigmentado Ocular/patología , Proteínas/genética , Especificidad de la EspecieRESUMEN
A dominant induced mutation in the mouse, tightly associated with a reciprocal chromosomal translocation between Chrs 4 and 17, causes abnormal head tossing and circling behavior (the translocation induced circling mutation, Tim). Affected mice develop an unusual anterior subcapsular cataract that appears after birth and is progressive. The most likely explanation for the phenotypic observations is that the translocation breakpoint disrupted a gene or its regulation. Although the Mos protooncogene is located close to the translocation breakpoint and transgenic mice that overexpress Mos demonstrate cataracts and circling behavior, there were no gross changes in the Mos gene or in its level of expression. The morphological changes observed in the lens resemble those seen in some human congenital cataract syndromes.
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Catarata/genética , Cromosomas/genética , Células Epiteliales/citología , Cristalino/metabolismo , Trisomía , Animales , Animales Recién Nacidos , Northern Blotting , Southern Blotting , División Celular , Aberraciones Cromosómicas , Trastornos de los Cromosomas , ADN/análisis , ADN/genética , Femenino , Cristalino/patología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBARESUMEN
Prox1, a vertebrate homologue of Drosophila prospero, encodes a divergent homeodomain protein. We have isolated and characterized full length mouse Prox1 cDNA and genomic clones. Mouse Prox1 gene mapped to position 106.3 cM from the centromere of Chromosome 1, which is very close to the retinal degeneration mutation, rd3. Although the coding sequence and exon-intron junctions of the Prox1 genes of wild type and rd3 mutant mice are identical, Northern blot analysis indicated that the ratio of the short (2.3 kb) and long (8 kb) forms of Prox1 mRNA is different in RNA isolated from wild type and rd3 retinas. Immunostaining of the eyes from wild type and rd3 animals also revealed differences in the distribution of Prox1 protein in the retina and lens. These data suggest that the rd3 mutation affects expression of the mouse Prox1 gene.
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Mapeo Cromosómico , Proteínas de Homeodominio/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Secuencia Conservada , ADN Complementario , Exones , Genes Homeobox , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/química , Humanos , Intrones , Cristalino/metabolismo , Ratones , Ratones Mutantes , Datos de Secuencia Molecular , ARN Mensajero/biosíntesis , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Retina/metabolismo , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Proteínas Supresoras de TumorRESUMEN
PURPOSE: To characterize ocular abnormalities associated with iris atrophy in DBA/2J mice and to determine whether mice of this strain develop elevated intraocular pressure (IOP) and glaucoma. METHODS: Different approaches, including slit-lamp biomicroscopy, ophthalmoscopic examination, ultrasound backscatter microscopy, and histology were used to examine the eyes of DBA/2J mice ranging from 2 to 30 months old. IOP was measured in DBA/2J mice of different ages. RESULTS: DBA/2J mice were found to develop pigment dispersion, iris transillumination, iris atrophy, anterior synechias, and elevated IOP. IOP was elevated in most mice by the age of 9 months. These changes were followed by the death of retinal ganglion cells, optic nerve atrophy, and optic nerve cupping. The prevalence and severity of these lesions increased with age. Optic nerve atrophy and optic nerve cupping was present in the majority of mice by the age of 22 months. CONCLUSIONS: DBA/2J mice develop a progressive form of secondary angle-closure glaucoma that appears to be initiated by iris atrophy and the associated formation of synechias. This mouse strain represents a useful model to evaluate mechanisms of pressure-related ganglion cell death and optic nerve atrophy, and to evaluate strategies for neuroprotection.
Asunto(s)
Síndrome de Exfoliación/patología , Enfermedades Hereditarias del Ojo/patología , Glaucoma de Ángulo Cerrado/patología , Iris/patología , Envejecimiento/patología , Animales , Segmento Anterior del Ojo/patología , Atrofia , Muerte Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Síndrome de Exfoliación/etiología , Síndrome de Exfoliación/genética , Enfermedades Hereditarias del Ojo/etiología , Enfermedades Hereditarias del Ojo/genética , Femenino , Glaucoma de Ángulo Cerrado/etiología , Glaucoma de Ángulo Cerrado/genética , Presión Intraocular , Masculino , Ratones , Ratones Endogámicos DBA , Hipertensión Ocular/etiología , Hipertensión Ocular/genética , Hipertensión Ocular/patología , Atrofia Óptica/etiología , Atrofia Óptica/patología , Células Ganglionares de la Retina/patologíaRESUMEN
An autosomal dominant retinal degeneration, called Rd4, was found in a stock carrying the inversion In(4)56Rk, which was induced in a DBA/2J male. The inversion encompasses nearly all of Chromosome 4. It is homozygous lethal and in heterozygotes is always associated with retinal degeneration. In affected mice, the retinal outer nuclear and plexiform layers begin to reduce at 10 days of age, showing total loss at 6 weeks. The recordable electroretinograms (ERG) showed poorly at 3 to 6 weeks and were barely detected after 6 weeks of age. Retinal vessel attenuation, pigment spots, and optic atrophy appeared in the fundus at 4 weeks of age. Rd4 has not recombined with the inversion in an outcross, suggesting that the Rd4 locus is located very close to or is disrupted by one of the breakpoints of the inversion, either near the centromere or near the telomere. A human homolog would be expected to be located on human chromosomes 1p or 8q.
Asunto(s)
Inversión Cromosómica , Genes Dominantes , Degeneración Retiniana/genética , Animales , Electrorretinografía , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Degeneración Retiniana/patología , Degeneración Retiniana/fisiopatologíaRESUMEN
To assess prenatal and postnatal developmental status in the offspring of a group of animals, it is typical to examine fetuses from some of the dams as well as infants born to the remaining dams. Statistical limitations often arise, particularly when the animals are rare or especially precious, because all offspring of the dam represent only a single statistical observation; littermates are not independent observations (biologically or statistically). We describe a study in which pregnant laboratory rats were laparotomized on day 7 of gestation (GD7) to ascertain the number and distribution of uterine implantation sites and were subjected to a simulated experience on a 10-day space shuttle flight. After the simulated landing on GD18, rats were unilaterally hysterectomized, thus providing a sample of fetuses from 10 independent uteruses, followed by successful vaginal delivery on GD22, yielding postnatal samples from 10 uteruses. A broad profile of maternal and offspring morphologic and physiologic measures indicated that these novel sampling procedures did not compromise maternal well-being and maintained normal offspring development and function. Measures included maternal organ weights and hormone concentrations, offspring body size, growth, organ weights, sexual differentiation, and catecholamine concentrations.