UNC45A deficiency causes microvillus inclusion disease–like phenotype by impairing myosin VB–dependent apical trafficking

International audienceVariants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45A(KO) Caco-2 cells. In keeping with impaired myosin VB function, UNC45A(KO) Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45A(KO) 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease

Sleep Problems in School-aged Children and Teenagers From Bogotá, Colombia Private Schools, and Screen Exposure During the COVID-19 Pandemic

1.Introducción A raíz de la pandemia de COVID-19, el gobierno colombiano impulsó el uso de tecnologías para evitar actividades presenciales en las escuelas. Este tiempo de pantalla aumentado exposición de pacientes de 9 a 17 años, posiblemente modificando sus patrones de sueño. No hay estudios anteriores. que describen alteraciones en los patrones de sueño y exposición al tiempo frente a pantallas de nuestra población en este contexto.2.MétodosSe realizó un estudio observacional transversal en participantes de 9 a 17 años. que estaban matriculados en colegios privados de Bogotá. Se envió una encuesta en línea a sus padres, lo que condujo a un cuestionario que incluía datos demográficos, preguntas sobre la exposición al tiempo de pantalla para actividades académicas y recreativas, y el cuestionario BEARS para evaluar la presencia de problemas relacionados con el sueño. Se realizó un análisis estadístico descriptivo.Q1Q11.Introduction As a result of the COVID-19 pandemic, Colombian government promoted the use of technologies to avoid physical-attendance activities in schools. This augmented screen-time exposure of patients ages 9-17, possibly modifying their sleep patterns. There aren’t former studies that describe alterations in the sleep patterns and screen-time exposure of our population in this context.2.MethodsAn observational, cross-sectional study was performed in participants aged 9-17 that were enrolled in private schools in Bogota. An online based survey was sent to their parents, which led to a questionnaire that included demographics, questions about screen-time exposure for academic and recreational activities, and the BEARS questionnaire to evaluate the presence of sleep-related problems. A descriptive statistical analysis was performed.Revista Internacional - IndexadaS