Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene leading to the presence of premature termination codons (PTC). Previous transcriptional studies have shown reduced DMD transcript levels in DMD patient and animal model muscles when PTC are present. Nonsense-mediated decay (NMD) has been suggested to be responsible for the observed reduction, but there is no experimental evidence supporting this claim. In this study, we aimed to investigate the mechanism responsible for the drop in DMD expression levels in the presence of PTC. We observed that the inhibition of NMD does not normalize DMD gene expression in DMD. Additionally, in situ hybridization showed that DMD messenger RNA primarily localizes in the nuclear compartment, confirming that a cytoplasmic mechanism like NMD indeed cannot be responsible for the observed reduction. Sequencing of nascent RNA to explore DMD transcription dynamics revealed a lower rate of DMD transcription in patient-derived myotubes compared to healthy controls, suggesting a transcriptional mechanism involved in reduced DMD transcript levels. Chromatin immunoprecipitation in muscle showed increased levels of the repressive histone mark H3K9me3 in mdx mice compared to wild-type mice, indicating a chromatin conformation less prone to transcription in mdx mice. In line with this finding, treatment with the histone deacetylase inhibitor givinostat caused a significant increase in DMD transcript expression in mdx mice. Overall, our findings show that transcription dynamics across the DMD locus are affected by the presence of PTC, hinting at a possible epigenetic mechanism responsible for this process.

Long-term remitted Cushing’s disease (LTRCD) patients commonly continue to present persistent psychological and cognitive deficits, and alterations in brain function and structure. Although previous studies have conducted gray matter volume analyses, assessing cortical thickness and surface area of LTRCD patients may offer further insight into the neuroanatomical substrates of Cushing’s disease. Structural 3T magnetic resonance images were obtained from 25 LTRCD patients, and 25 age-, gender-, and education-matched healthy controls (HCs). T1-weighted images were segmented using FreeSurfer software to extract mean cortical thickness and surface area values of 68 cortical gray matter regions and two whole hemispheres. Paired sample t tests explored differences between the anterior cingulate cortex (ACC; region of interest), and the whole brain. Validated scales assessed psychiatric symptomatology, self-reported cognitive functioning, and disease severity. After correction for multiple comparisons, ROI analyses indicated that LTRCD-patients showed reduced cortical thickness of the left caudal ACC and the right rostral ACC compared to HCs. Whole-brain analyses indicated thinner cortices of the left caudal ACC, left cuneus, left posterior cingulate cortex, right rostral ACC, and bilateral precuneus compared to HCs. No cortical surface area differences were identified. Cortical thickness of the left caudal ACC and left cuneus were inversely associated with anxiety symptoms, depressive symptoms, and disease duration, although certain associations did not persist after correction for multiple testing. In six of 68 regions examined, LTRCD patients had reduced cortical thickness in comparison to HCs. Cortical thickness of the left caudal ACC was inversely associated with disease duration. This suggests that prolonged and excessive exposure to glucocorticoids may be related to cortical thinning of brain structures involved in emotional and cognitive processing.

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IntroductionRemitted Cushing’s disease (RCD)-patients commonly continue to present persistent psychological and cognitive deficits, and alterations in brain function and structure. Assessing cortical thickness and surface area of RCD-patients may offer further insight into the neuroanatomical substrates of Cushing’s disease.ObjectivesTo assess cortical thickness and surface area in RCD-patients in comparison to healthy controls (HCs).MethodsStructural 3T MRI’s were obtained from 25 long-term RCD-patients, and 25 age-, gender-, and education-matched HCs. T1-weighted images were segmented to extract mean cortical thickness and surface area values of 68 cortical gray matter regions. Paired sample t-tests explored differences between the anterior cingulate cortex (ACC; region of interest), and the whole brain. Validated scales assessed psychiatric symptomatology, self-reported cognitive functioning, and disease severity.ResultsAfter correction for multiple comparisons, ROI analyses indicated that RCD-patients showed reduced cortical thickness of the left caudal ACC and the right rostral ACC compared to HCs. Whole-brain analyses indicated thinner cortices of the left caudal ACC, left cuneus, left posterior cingulate cortex, right rostral ACC, and bilateral precuneus compared to HCs. No cortical surface area differences were identified. Cortical thickness of the left caudal ACC was inversely associated with anxiety symptoms and disease duration.ConclusionsIn six of 68 regions examined, RCD patients had reduced cortical thickness in comparison to HCs. Cortical thickness of the left caudal ACC was inversely associated with disease duration, suggesting that prolonged and excessive exposure to glucocorticoids may be related to cortical thinning of brain structures involved in emotional and cognitive processing.DisclosureNo significant relationships.

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