In Huntington's disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.

INTRODUCTION Individuals with isolated cleft lip and/or palate (ICLP) are often reported to be of shorter stature relative to peers, and the objective of this study was to explore the role of the pituitary in relationship to growth. METHODS Fifty-five males and 32 females with ICLP were compared to 121 healthy males and 158 healthy females with respect to height and BMI. Magnetic resonance imaging (MRI) scans were obtained from all ICLP participants and 47% of healthy group participants. RESULTS Males with ICLP were shorter than healthy males and had lower BMI. However, the trajectories for height and BMI did not differ between groups. Analyses in a separate sample of adult males suggested that height normalizes in males with ICLP in their early 30s. There were no differences in mean pituitary volume and pituitary trajectories between male groups. Females with ICLP were shorter than healthy females and also had slower growth rates. They did not differ in mean BMI or BMI trajectories. Furthermore, there were no differences in mean pituitary volume, or in pituitary trajectories. DISCUSSION Our findings suggest that there are no gross morphological differences in pituitary volume in individuals with ICLP, although more subtle differences may exist.

Orofacial clefts are among the commonest birth defects. Among many genetic contributors to orofacial clefting, Interferon Regulatory Factor 6 (IRF6) is unique since mutations in this gene cause Van der Woude (VWS), the most common clefting syndrome. Furthermore, variants in IRF6 contribute to increased risk for non-syndromic cleft lip and/or palate (NSCL/P). Our previous work shows that individuals with either VWS or NSCL/P may have cerebral anomalies (larger anterior, smaller posterior regions), and a smaller cerebellum. The objective of this study was to test the hypothesis that disrupting Irf6 in the mouse will result in quantitative brain changes similar to those reported for humans with VWS and NSCL/P. Male mice heterozygous for Irf6 (Irf6gt1/+; n = 9) and wild type (Irf6+/+; n = 6) mice at comparable age underwent a 4.7T MRI scan to obtain quantitative measures of cortical and subcortical brain structures. There was no difference in total brain volume between groups. However, the frontal cortex was enlarged in the Irf6gt1/+ mice compared to that of wild types (p = 0.028) while the posterior cortex did not differ. In addition, the volume of the cerebellum of Irf6gt1/+ mice was decreased (p = 0.004). Mice that were heterozygous for Irf6 showed a similar pattern of brain anomalies previously reported in humans with VWS and NSCL/P. These structural differences were present in the absence of overt oral clefts. These results support a role for IRF6 in brain morphometry and provide evidence for a potential genetic link to abnormal brain development in orofacial clefting.

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