Effect of genetic background on the dystrophic phenotype in mdx mice.

Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan-null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them with the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared with their respective control strains at multiple time points between 6 and 52 weeks of age. Skeletal and cardiac muscle function, inflammation, regeneration, histology and biochemistry were characterized. We found that D2-mdx mice showed significantly reduced skeletal muscle function as early as 7 weeks and reduced cardiac function by 28 weeks, suggesting that the disease phenotype is more severe than in B10-mdx mice. In addition, D2-mdx mice showed fewer central myonuclei and increased calcifications in the skeletal muscle, heart and diaphragm at 7 weeks, suggesting that their pathology is different from the B10-mdx mice. The new D2-mdx model with an earlier onset and more pronounced dystrophy phenotype may be useful for evaluating therapies that target cardiac and skeletal muscle function in dystrophin-deficient mice. Our data align the D2-mdx with Duchenne muscular dystrophy patients with the LTBP4 genetic modifier, making it one of the few instances of cross-species genetic modifiers of monogenic traits.

Deficits in auditory processing contribute to impairments in vocal affect recognition in autism spectrum disorders: A MEG study.

OBJECTIVE: The primary aim of this study was to examine whether there is an association between magnetoencephalography-based (MEG) indices of basic cortical auditory processing and vocal affect recognition (VAR) ability in individuals with autism spectrum disorder (ASD). METHOD: MEG data were collected from 25 children/adolescents with ASD and 12 control participants using a paired-tone paradigm to measure quality of auditory physiology, sensory gating, and rapid auditory processing. Group differences were examined in auditory processing and vocal affect recognition ability. The relationship between differences in auditory processing and vocal affect recognition deficits was examined in the ASD group. RESULTS: Replicating prior studies, participants with ASD showed longer M1n latencies and impaired rapid processing compared with control participants. These variables were significantly related to VAR, with the linear combination of auditory processing variables accounting for approximately 30% of the variability after controlling for age and language skills in participants with ASD. CONCLUSIONS: VAR deficits in ASD are typically interpreted as part of a core, higher order dysfunction of the "social brain"; however, these results suggest they also may reflect basic deficits in auditory processing that compromise the extraction of socially relevant cues from the auditory environment. As such, they also suggest that therapeutic targeting of sensory dysfunction in ASD may have additional positive implications for other functional deficits.