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Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.
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Encefalitis/genética , Enfermedades Mitocondriales/genética , Animales , Evolución Biológica , Sistemas CRISPR-Cas , Línea Celular , Encefalitis/mortalidad , Femenino , Genes Recesivos , Glucógeno/metabolismo , Humanos , Inflamación/genética , Masculino , Proteínas de la Membrana/genética , Enfermedades Mitocondriales/mortalidad , Linaje , Convulsiones/genética , Convulsiones/mortalidad , Pez Cebra/genéticaRESUMEN
BACKGROUND: Carpal tunnel syndrome (CTS) is the most common type of peripheral nerve compression. Magnetic resonance imaging (MRI) is becoming more popular in practice in the evaluation of CTS. PURPOSE: To evaluate the diagnostic value of MRI in CTS. MATERIAL AND METHODS: A cross-sectional study of 39 wrists was conducted. Clinical and nerve conduction study findings were evaluated and graded according to the Boston Carpal Tunnel Questionnaire (BCTQ) and the American Association of Neuromuscular and Electrodiagnostic Medicine. MRI was performed using a 1.5-T scanner. MRI parameters included cross-sectional area (CSA) of the median nerve and the ratio change in CSA at four levels: distal radioulnar joint (DRUJ-CSA); pisiform (p-CSA); middle of the carpal tunnel (i-CSA); and hook of hamate. The ratio change in CSA was expressed as p-CSA/DRUJ-CSA and ΔCSA (difference between iCSA and DRUJ-CSA), the flattening ratio of the median nerve, the thickness of the flexor retinaculum, flexor retinaculum bowing ratio, signal intensity ratio of the median, nerve and hypothenar muscle signal intensity. RESULTS: With a cutoff point of 10.9 mm2 of the p-CSA, MRI had a sensitivity and specificity of 97.4% and 80% for diagnosis of CTS, respectively. There was a significant association between the clinical and electrophysiological stage with MRI findings (P < 0.001). There was a positive correlation between the BCTQ score and MRI parameters (0.5 < r < 0.7, P < 0.01). CONCLUSION: MRI has good diagnostic value in evaluating CTS. We recommend using p-CSA ≥10.9 mm2 and ΔCSA ≥2.3 mm2 as MRI diagnostic criteria of CTS.
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Síndrome del Túnel Carpiano , Humanos , Síndrome del Túnel Carpiano/diagnóstico por imagen , Estudios Transversales , Nervio Mediano/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Muñeca , UltrasonografíaRESUMEN
Structural maintenance of chromosomes flexible hinge domain-containing 1 (Smchd1) plays important roles in epigenetic silencing and normal mammalian development. Recently, heterozygous mutations in SMCHD1 have been reported in two disparate disorders: facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS). FSHD2-associated mutations lead to loss of function; however, whether BAMS is associated with loss- or gain-of-function mutations in SMCHD1 is unclear. Here, we have assessed the effect of SMCHD1 missense mutations from FSHD2 and BAMS patients on ATP hydrolysis activity and protein conformation and the effect of BAMS mutations on craniofacial development in a Xenopus model. These data demonstrated that FSHD2 mutations only result in decreased ATP hydrolysis, whereas many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus Interestingly, a mutation reported in both an FSHD2 patient and a BAMS patient results in increased ATPase activity and a smaller Xenopus eye size. Mutations in the extended ATPase domain increased catalytic activity, suggesting critical regulatory intramolecular interactions and the possibility of targeting this region therapeutically to boost SMCHD1's activity to counter FSHD.
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Adenosina Trifosfato/metabolismo , Atresia de las Coanas/genética , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/metabolismo , Oftalmopatías/patología , Microftalmía/genética , Distrofia Muscular Facioescapulohumeral/genética , Mutación Missense , Nariz/anomalías , Adenosina Trifosfatasas , Secuencia de Aminoácidos , Animales , Atresia de las Coanas/patología , Proteínas Cromosómicas no Histona/genética , Cristalografía por Rayos X , Oftalmopatías/genética , Oftalmopatías/metabolismo , Humanos , Ratones , Microftalmía/patología , Distrofia Muscular Facioescapulohumeral/patología , Nariz/patología , Conformación Proteica , Dominios Proteicos , Homología de Secuencia , Xenopus laevisRESUMEN
Background: Among pharmacy workers, low workplace wellbeing can lead to reduced effectiveness. However, to date, studies on this issue are limited within the community pharmacy setting in Vietnam. Objectives: This study was conducted to identify the component aspects of workplace wellbeing and their associations with demographic characteristics. Methods: The cross-sectional descriptive study was conducted in Can Tho, Vietnam. Self-administered questionnaires were hand-delivered to all pharmacy workers working at selected community pharmacies. The workplace wellbeing scale comprised 18 items. Results: In total, 382 pharmacy workers participated in this study. Factor analysis revealed three fundamental aspects to workplace wellbeing: Factor 1 - perceived self-worth and job satisfaction, Factor 2 - positive emotions with work, and Factor 3 - negative emotions with work. Factor 1 showed a positive correlation with Factor 2, with a correlation coefficient (ρ) of 0.509, while both Factor 1 (ρ = -0.399) and Factor 2 (ρ = -0.416) demonstrated negative correlations with Factor 3. Higher income was associated with higher positive emotions with work (P = 0.008), higher perceived self-worth and job satisfaction (P = 0.013), and lower negative emotions with work (P < 0.001). Conclusion: Workplace wellbeing of pharmacy workers in their professional environments was associated with financial aspects. These findings suggest that policies aimed at improving income for pharmacy workers could bring benefits to enhancing job satisfaction and workplace wellbeing.
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The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at the facioscapulohumeral muscular dystrophy associated macrosatellite-array, D4Z4, resulting in enhanced repression of DUX4 encoded by this repeat. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against other epigenetic regulators, including PRC2 and CTCF, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1's role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease.
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Cromatina , Proteínas Cromosómicas no Histona , Distrofia Muscular Facioescapulohumeral , Animales , Ratones , Cromatina/genética , Epigenómica , Silenciador del Gen , Genes Homeobox , Distrofia Muscular Facioescapulohumeral/genética , Proteínas Cromosómicas no Histona/genéticaRESUMEN
[This corrects the article DOI: 10.1016/j.radcr.2020.10.044.].
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The body plan of animals is laid out by an evolutionary-conserved HOX code which is colinearly transcribed after zygotic genome activation (ZGA). Here we report that SMCHD1, a chromatin-modifying enzyme needed for X-inactivation in mammals, is maternally required for timely HOX expression. Using zebrafish and mouse Smchd1 knockout animals, we demonstrate that Smchd1 haplo-insufficiency brings about precocious and ectopic HOX transcription during oogenesis and embryogenesis. Unexpectedly, wild-type offspring born to heterozygous knockout zebrafish smchd1 mothers exhibited patent vertebrate patterning defects. The loss of maternal Smchd1 was accompanied by HOX epi-mutations driven by aberrant DNA methylation. We further show that this regulation is mediated by Lrif1, a direct interacting partner of Smchd1, whose knockout in zebrafish phenocopies that of Smchd1. Rather than being a short-lived maternal effect, HOX mis-regulation is stably inherited through cell divisions and persists in cultured fibroblasts derived from FSHD2 patients haploinsufficient for SMCHD1. We conclude that maternal SMCHD1/LRIF1 sets up an epigenetic state in the HOX loci that can only be reset in the germline. Such an unusual inter-generational inheritance, whereby a phenotype can be one generation removed from its genotype, casts a new light on how unresolved Mendelian diseases may be interpreted.
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Proteínas Cromosómicas no Histona , Genes Homeobox , Haploinsuficiencia , Distrofia Muscular Facioescapulohumeral , Animales , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Epigénesis Genética , Humanos , Ratones , Distrofia Muscular Facioescapulohumeral/genética , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genéticaRESUMEN
White matter hyperintensities (WMH) are the focus of intensive research and have been linked to cognitive impairment and depression in the elderly. Cumbersome manual outlining procedures make research on WMH labour intensive and prone to subjective bias. This study compares fully automated supervised detection methods that learn to identify WMH from manual examples against unsupervised approaches on the combination of FLAIR and T1 weighted images. Data were collected from ten subjects with mild cognitive impairment and another set of ten individuals who fulfilled diagnostic criteria for dementia. Data were split into balanced groups to create a training set used to optimize the different methods. Manual outlining served as gold standard to evaluate performance of the automated methods that identified each voxel either as intact or as part of a WMH. Otsu's approach for multiple thresholds which is based only on voxel intensities of the FLAIR image produced a high number of false positives at grey matter boundaries. Performance on an independent test set was similarly disappointing when simply applying a threshold to the FLAIR that was found from training data. Among the supervised methods, precision-recall curves of support vector machines (SVM) indicated advantages over the performance achieved by K-nearest-neighbor classifiers (KNN). The curves indicated a clear benefit from optimizing the threshold of the SVM decision value and the voting rule of the KNN. Best performance was reached by selecting training voxels according to their distance to the lesion boundary and repeated training after replacing the feature vectors from those voxels that did not form support vectors of the SVM. The study demonstrates advantages of SVM for the problem of detecting WMH at least for studies that include only FLAIR and T1 weighted images. Various optimization strategies are discussed and compared against each other.