RESUMEN
The toxic proline:arginine (PRn) poly-dipeptide encoded by the (GGGGCC)n repeat expansion in the C9orf72 form of heritable amyotrophic lateral sclerosis (ALS) binds to the central channel of the nuclear pore and inhibits the movement of macromolecules into and out of the nucleus. The PRn poly-dipeptide binds to polymeric forms of the phenylalanine:glycine (FG) repeat domain, which is shared by several proteins of the nuclear pore complex, including those in the central channel. A method of chemical footprinting was used to characterize labile, cross-ß polymers formed from the FG domain of the Nup54 protein. Mutations within the footprinted region of Nup54 polymers blocked both polymerization and binding by the PRn poly-dipeptide. The aliphatic alcohol 1,6-hexanediol melted FG domain polymers in vitro and reversed PRn-mediated enhancement of the nuclear pore permeability barrier. These data suggest that toxicity of the PRn poly-dipeptide results in part from its ability to lock the FG repeats of nuclear pore proteins in the polymerized state. Our study offers a mechanistic interpretation of PRn poly-dipeptide toxicity in the context of a prominent form of ALS.
Asunto(s)
Transporte Activo de Núcleo Celular , Proteína C9orf72/farmacología , Expansión de las Repeticiones de ADN/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Poro Nuclear/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Biopolímeros , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Dipéptidos/genética , Dipéptidos/metabolismo , Dipéptidos/farmacología , Femenino , Glicoles/farmacología , Humanos , Microscopía Confocal , Poro Nuclear/química , Poro Nuclear/efectos de los fármacos , Poro Nuclear/ultraestructura , Proteínas de Complejo Poro Nuclear/química , Proteínas de Complejo Poro Nuclear/ultraestructura , Oocitos/ultraestructura , Permeabilidad/efectos de los fármacos , Unión Proteica , Dominios Proteicos , Aglutininas del Germen de Trigo/metabolismo , Aglutininas del Germen de Trigo/farmacología , Xenopus laevisRESUMEN
Erythema elevatum diutinum (EED) is a rare, cutaneous vasculitis of uncertain origin. EED can present clinically as chronic bilateral, symmetrical, periarticular papules, plaques and nodules. We report here an unusual case of EED presenting as multiple, densely fibrosing nodules on the feet of a 60-year-old human immunodeficiency virus positive woman. The initial evaluation of the patient was complicated by the strong histologic resemblance of multiple lesions to sclerotic fibroma, a cutaneous manifestation of Cowden disease. Our case highlights the important features that distinguish these 2 pathologic entities.
Asunto(s)
Infecciones por VIH/complicaciones , Huésped Inmunocomprometido , Vasculitis Leucocitoclástica Cutánea/inmunología , Vasculitis Leucocitoclástica Cutánea/patología , Diagnóstico Diferencial , Femenino , Fibroma/diagnóstico , Fibroma/patología , Síndrome de Hamartoma Múltiple/diagnóstico , Síndrome de Hamartoma Múltiple/patología , Humanos , Persona de Mediana Edad , Vasculitis Leucocitoclástica Cutánea/diagnósticoRESUMEN
The nail unit and genitalia represent rare locations where malignant tumors may arise. Human papillomavirus has emerged as a causative agent of the development of the most common malignancies in these sites. Tissue preservation with surgery is of utmost importance, and tissue-sparing approaches are increasingly emphasized in the dermatology, urology, and gynecology literature. In addition to its tissue-sparing nature, Mohs micrographic surgery allows the complete evaluation of histologic margins to ensure tumor extirpation and may be the ideal treatment modality. The authors herein present approaches for the evaluation and treatment of malignant tumors of the nail unit and genitalia.