RESUMEN
Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.
Asunto(s)
Colon/fisiología , Genes Modificadores/genética , Genotipo , Enfermedades Inflamatorias del Intestino/genética , NADPH Oxidasa 1/genética , Animales , Niño , Preescolar , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genoma , Secuenciación de Nucleótidos de Alto Rendimiento , Interacciones Huésped-Patógeno , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación Missense/genética , Polimorfismo de Nucleótido Simple , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Dermatomycosis in domestic animals are important zoonosis in view of the fact that they maintain close contact with human beings. Seven ringworm outbreaks are here described, one of M. gypseum involving a cat and a women and the remainder of M. canis involving 20 human beings (adults, young people and children), 5 dogs, 16 cats and a gibbon-monkey (Hylobates lar).
Asunto(s)
Dermatomicosis/epidemiología , Brotes de Enfermedades/estadística & datos numéricos , Microsporum/aislamiento & purificación , Adolescente , Adulto , Animales , Brasil/epidemiología , Enfermedades de los Gatos/microbiología , Gatos , Niño , Preescolar , Dermatomicosis/microbiología , Dermatomicosis/veterinaria , Enfermedades de los Perros/microbiología , Perros , Femenino , Humanos , Hylobates , Masculino , Enfermedades de los Monos/microbiología , Piel/microbiologíaRESUMEN
As dermatomicoses dos animais domésticos constituem zoonoses importantes, uma vez que estes mantêm estreito contato com a espécie humana, dada a alta infectividade observada nesses processos. Relata-se ocorrência de sete surtos de dermatomicoses, um por M. gypseum envolvendo um gato e um indivíduo do sexo feminino e os outros por M. canis envolvendo 20 indivíduos da espécie humana (adultos, jovens e crianças de ambos os sexos), 5 cäes, 16 gatos e um macaco gibäo (Hylobates lar)