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Fragile X syndrome (FXS) is a monogenic disease caused by mutations in the FMR1 gene. The Fmr1 knockout (KO) mice show many aspects of FXS-related phenotypes, and have been used as a major pre-clinical model for FXS. Although FXS occurs in both male and female patients, most studies on the mouse model use male animals. Few studies test whether gender affects the face validity of the mouse model. Here, we examined multiple behavioral phenotypes with male hemizygous and female homozygous Fmr1 KO mice on C57BL/6 background. For each behavioral paradigm, we examined multiple cohorts from different litters. We found that both male and female Fmr1 KO mice displayed significant audiogenic seizures, hyperactivity in the open field test, deficits in passive avoidance and contextual fear memory, and significant enhancement of PPI at low stimulus intensity. Male and female Fmr1 KO mice also showed more transitional movement between the lit and dark chambers in the light-dark tests. The lack of gender effects suggests that the Fmr1 KO mouse is a reasonable tool to test the efficacy of potential FXS therapies. [ABSTRACT FROM AUTHOR]

Abstract: Autism is the short name of a complex and heterogeneous group of disorders (autism spectrum disorders, ASD) with several lead symptoms required for classification, including compromised social interaction, reduced verbal communication and stereotyped repetitive behaviors/restricted interests. The etiology of ASD is still unknown in most cases but monogenic heritable forms exist that have provided insights into ASD pathogenesis and have led to the notion of autism as a ‘synapse disorder’. Among the most frequent monogenic causes of autism are loss-of-function mutations of the NLGN4X gene which encodes the synaptic cell adhesion protein neuroligin-4X (NLGN4X). We previously described autism-like behaviors in male Nlgn4 null mutant mice, including reduced social interaction and ultrasonic communication. Here, we extend the phenotypical characterization of Nlgn4 null mutant mice to both genders and add a series of additional autism-relevant behavioral readouts. We now report similar social interaction and ultrasonic communication deficits in females as in males. Furthermore, aggression, nest-building parameters, as well as self-grooming and circling as indicators of repetitive behaviors/stereotypies were explored in both genders. The construction of a gender-specific autism severity composite score for Nlgn4 mutant mice markedly diminishes population/sample heterogeneity typically obtained for single tests, resulting in p values of <0.00001 and a genotype predictability of 100% for male and of >83% for female mice. Taken together, these data underscore the similarity of phenotypical consequences of Nlgn4/NLGN4X loss-of-function in mouse and man, and emphasize the high relevance of Nlgn4 null mutant mice as an ASD model with both construct and face validity. [Copyright &y& Elsevier]

The muscular dystrophies are a clinically and histologically well characterized group of genetic diseases, with predominantly monogenic etiologies. Many causative gene mutations have been already identified, but the underlying pathophysiological pathways and phenotypic variability in each form are much more complex, suggesting the involvement of many other genes. Thus, study the whole genome expression profile can significantly contribute to: identify altered biological functions which could contribute to the understanding of the disease; identify possible prognostic biomarkers and find points for therapeutic intervention. Here, we present the first global gene expression analysis of the muscle of MD mouse models: Large myd (CMD1D), Dmd mdx /Large myd (double mutant for DMD and CMD1D) compared to Dmd mdx (model for Duchenne MD) and normal C57BL , in three different ages: 21 days, 3 and 6 months. Five animals from each group were analyzed using DNA microarrays. The data were preprocessed and normalized in Expression Console software and screening of DEGs was done with SAM method. In general, a predominance of upregulated than downregulated genes was observed in the dystrophic muscles, compatible with high rates of protein turnover that could occur due to the subsequent activation of regeneration process. The Large myd and Dmd mdx /Large myd mice present a progressive increase in the number of differentially expressed genes (DEGs) with aging. The analysis done between Dmd mdx / Large myd and its parental lineages Dmd mdx and Large myd showed the smallest number of DEGs, suggesting that the reason of its worst phenotype is controlled by the expression of a few but very important genes. Preliminary functional analyses in IPA and Expander softwares showed a high proportion of genes involved in immune and inflammatory pathways in all lineages that could be explained by the intense dystrophic process. [ABSTRACT FROM AUTHOR]