Smallie (slie), a spontaneous, autosomal-recessive mutation causes dwarfing and infertility in mice. The purpose of this study was to determine and characterize the underlying molecular genetic basis for its phenotype. The slie locus was mapped to chromosome 1, and fine-structure mapping narrowed the slie allele within 2 Mb between genetic markers D1Mit36 and Mpz. To pinpoint the underlying mutation quantitative real-time PCR was used to measure the relative expression levels for the genes residing within this region. Expression of one gene, Ddr2, which encodes discoidin domain receptor 2 (DDR2), was absent in slie homozygote mice. Genomic sequencing analysis detected a 150-kb deletion that extended into the Ddr2 gene transcript. Detailed phenotype analysis revealed that gonadal dysregulation underlies infertility in slie mice because all females were anovulatory and most adult males lacked spermatogenesis. The pituitary gland of prepubertal slie mice was smaller than in wild-type mice. The basal levels and gene expression for pituitary and hypothalamic hormones, and gene expression for hypothalamic-releasing hormones, were not significantly different between slie and wild-type mice. Circulating levels of IGF-1 did not differ in slie mice despite lower Igf-1 mRNA expression in the liver. After exogenous gonadotropin administration, the levels of secreted steroid hormones in both male and female adult slie mice were blunted compared to adult wild-type, but was similar to prepubertal wild-type mice. Taken together, our results indicate that the absence of DDR2 leads to growth retardation and gonadal dysfunction due to peripheral defects in hormonal-responsive pathways in slie mice.

No abstract

Idiopathic epilepsy is a common human disorder with a strong genetic component, usually exhibiting complex inheritance. We describe a new mouse mutation in C57BL/6J mice, called frequent-flyer (Ff), in which disruption of the gene encoding RNA-binding protein Bruno-like 4 (Brunol4) leads to limbic and severe tonic–clonic seizures in heterozygous mutants beginning in their third month. Younger heterozygous adults have a reduced seizure threshold. Although homozygotes do not survive well on the C57BL/6J background, on mixed backgrounds homozygotes and some heterozygotes also display spike-wave discharges, the electroencephalographic manifestation of absence epilepsy. Brunol4 is widely expressed in the brain with enrichment in the hippocampus. Gene expression profiling and subsequent analysis revealed the down-regulation of at least four RNA molecules encoding proteins known to be involved in neuroexcitability, particularly in mutant hippocampus. Genetic and phenotypic assessment suggests that Brunol4 deficiency in mice results in a complex seizure phenotype, likely due to the coordinate dysregulation of several molecules, providing a unique new animal model of epilepsy that mimics the complex genetic architecture of common disease.

The Mouse Phenome Database (MPD; http://www.jax.org/phenome) is an open source, web-based repository of phenotypic and genotypic data on commonly used and genetically diverse inbred strains of mice and their derivatives. MPD is also a facility for query, analysis and in silico hypothesis testing. Currently MPD contains about 1400 phenotypic measurements contributed by research teams worldwide, including phenotypes relevant to human health such as cancer susceptibility, aging, obesity, susceptibility to infectious diseases, atherosclerosis, blood disorders and neurosensory disorders. Electronic access to centralized strain data enables investigators to select optimal strains for many systems-based research applications, including physiological studies, drug and toxicology testing, modeling disease processes and complex trait analysis. The ability to select strains for specific research applications by accessing existing phenotype data can bypass the need to (re)characterize strains, precluding major investments of time and resources. This functionality, in turn, accelerates research and leverages existing community resources. Since our last NAR reporting in 2007, MPD has added more community-contributed data covering more phenotypic domains and implemented several new tools and features, including a new interactive Tool Demo available through the MPD homepage (quick link: http://phenome.jax.org/phenome/trytools).

The Mouse Phenome Database (MPD; ) is a repository of phenotypic and genotypic data on commonly used and genetically diverse inbred strains of mice. Strain characteristics data are contributed by members of the scientific community. Electronic access to centralized strain data enables biomedical researchers to choose appropriate strains for many systems-based research applications, including physiological studies, drug and toxicology testing and modeling disease processes. MPD provides a community data repository and a platform for data analysis and in silico hypothesis testing. The laboratory mouse is a premier genetic model for understanding human biology and pathology; MPD facilitates research that uses the mouse to identify and determine the function of genes participating in normal and disease pathways.