ABSTRACT
BACKGROUND: Little is known about genetic factors affecting intraocular pressure (IOP) in mice and other mammals. The purpose of this study was to determine the IOPs of genetically distinct mouse strains, assess the effects of factors such as age, sex and time of day on IOP in specific strain backgrounds, and to assess the effects of specific candidate gene mutations on IOP. RESULTS: Based on over 30 studied mouse strains, average IOP ranges from approximately 10 to 20 mmHg. Gender does not typically affect IOP and aging results in an IOP decrease in some strains. Most tested strains exhibit a diurnal rhythm with IOP being the highest during the dark period of the day. Homozygosity for a null allele of the carbonic anhydrase II gene (Car2n) does not alter IOP while homozygosity for a mutation in the leptin receptor gene (Leprdb) that causes obesity and diabetes results in increased IOP. Albino C57BL/6J mice homozygous for a tyrosinase mutation (Tyrc-2J) have higher IOPs than their pigmented counterparts. CONCLUSIONS: Genetically distinct mouse strains housed in the same environment have a broad range of IOPs. These IOP differences are likely due to interstrain genetic differences that create a powerful resource for studying the regulation of IOP. Age, time of day, obesity and diabetes have effects on mouse IOP similar to those in humans and other species. Mutations in two of the assessed candidate genes (Lepr and Tyr) result in increased IOP. These studies demonstrate that mice are a practical and powerful experimental system to study the genetics of IOP regulation and disease processes that raise IOP to harmful levels.
Subject(s)
Intraocular Pressure , Mice, Inbred Strains , Models, Animal , Age Factors , Anesthesia , Animals , Blood Pressure , Cytoskeletal Proteins , Environment , Eye Proteins/genetics , Female , Genetic Variation , Glaucoma/genetics , Glycoproteins/genetics , Intraocular Pressure/genetics , Male , Mice , Mice, Inbred Strains/genetics , Mice, Inbred Strains/physiology , Monophenol Monooxygenase/deficiency , Mutation , Periodicity , Rats , Reproducibility of Results , Risk Factors , Sex Factors , Species Specificity , Time FactorsABSTRACT
Mice homozygous for the fat mutation develop obesity and hyperglycaemia that can be suppressed by treatment with exogenous insulin. The fat mutation maps to mouse chromosome 8, very close to the gene for carboxypeptidase E (Cpe), which encodes an enzyme (CPE) that processes prohormone intermediates such as proinsulin. We now demonstrate a defect in proinsulin processing associated with the virtual absence of CPE activity in extracts of fat/fat pancreatic islets and pituitaries. A single Ser202Pro mutation distinguishes the mutant Cpe allele, and abolishes enzymatic activity in vitro. Thus, the fat mutation represents the first demonstration of an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway.
Subject(s)
Carboxypeptidases/genetics , Mutation , Proinsulin/blood , Amino Acid Sequence , Animals , Base Sequence , Carboxypeptidase B , Carboxypeptidase H , Carboxypeptidases/metabolism , Cattle , Chromosome Mapping , Conserved Sequence , Enzyme Activation , Female , Islets of Langerhans/enzymology , Islets of Langerhans/ultrastructure , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Obese , Mice, SCID , Molecular Sequence Data , Mutagenesis, Site-Directed , Pituitary Gland/enzymology , Proinsulin/metabolism , Rats , Sequence Alignment , TransfectionABSTRACT
BACKGROUND: Occupational allergy to mice is a major cause of disability among workers in mouse breeding and research facilities. Efforts to prevent and treat allergy require a detailed knowledge of exposure levels to allergen. OBJECTIVE: This study was designed to quantitate the level of major mouse allergen (Mus m I) in central room air and immediate breathing zones under a variety of working conditions. METHODS: An Andersen sampler (Groseby Andersen, Spirotech Div., Atlanta, Ga.) was used to collect allergen in each room. A Gillian Personal sampler (Gillian Instrument Corp., West Caldwell, N.J.) collected particles in the worker breathing zone. ELISA was used to quantitate the concentration of Mus m I collected on the two collection devices. RESULTS: Total Mus m I recovered from Andersen samplers ranged from 0.2 to 1.5 ng/m3 in rooms without mice and 0.5 to 15.1 ng/m3 in rooms with mice. Allergen recovered from the zone of worker activity ranged from 1.2 to 2.7 ng/m3 in rooms without mice and from 16.6 to 563.0 ng/m3 in rooms with mice. Direct mouse contact was associated with the highest levels of exposure to Mus m I. Analysis revealed the bulk of allergen to be in mid-particle size ranges (3.3 to 10 microns) for mouse-containing rooms and in small particle size range (0.43 to 3.3 microns) for non-mouse-containing rooms, suggesting that small particles were carried along corridors from rooms with mice into non-mouse-containing rooms. Ventilation characteristics of rooms and mouse population density were evaluated with a "mouse loading" index (number of mice per cubic meter of ventilated air per hour). Mouse loading correlated strongly with small particles (< 3.3 microns) in ambient air. CONCLUSIONS: Mus m I is widely distributed within mouse breeding facilities. Direct worker contact with mice seems to be the major factor in high level exposure.
