RESUMEN
OBJECTIVES: To characterize the clinical and cellular phenotypes of a novel MPZ mutation identified in a Chinese family with Charcot-Marie-Tooth (CMT) disease type 1B. METHODS: The family was evaluated clinically, electrophysiologically, pathologically, and genetically. The wild-type and mutant P(0) fused with fluorescent proteins were expressed in vitro to monitor their intracellular trafficking. Adhesion assay was also performed to evaluate the adhesiveness of cells. RESULTS: The novel MPZ mutation, c.367G>A, is associated with a late-onset demyelinating CMT phenotype with autosomal dominant inheritance. The median motor nerve conduction velocities of patients in this family ranged from 15.7 to 19.6 m/second. The neuropathologic studies from a sural nerve biopsy revealed a severe loss of myelinated fibers, and some onion bulb formation with clusters of regenerative fibers. Fluorescence analysis demonstrated that the mutant protein was retained ectopically in the endoplasmic reticulum and Golgi apparatus. Adhesion assay demonstrated a defective adhesiveness of cells expressing the mutant P(0)G123S protein. CONCLUSION: The novel P(0)G123S mutation is associated with typical findings of late-onset demyelinating polyneuropathy in the electrophysiologic and pathologic studies, putatively resulting from aberrant intracellular trafficking of the mutant P(0) protein, which compromises the adhesiveness of the cells.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Proteína P0 de la Mielina/genética , Adolescente , Adulto , Animales , Pueblo Asiatico/genética , Células CHO , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/metabolismo , Niño , China , Cricetinae , Cricetulus , Análisis Mutacional de ADN , Femenino , Marcadores Genéticos/genética , Pruebas Genéticas , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/genética , Linaje , Nervios Periféricos/metabolismo , Nervios Periféricos/patología , Nervios Periféricos/fisiopatologíaRESUMEN
Caspases have been known for several years for their involvement in executing apoptosis, where unwanted or damaged cells are eliminated. Surprisingly, after analysis of the relevant data set from the Stanford microarray database, we noticed that the gene expression pattern for caspase 3, but not for caspase 1, 6, 7, 8, 9, or 10, undergoes periodic change in the HeLa cell cycle. In this study, we have demonstrated that caspase 3, but not other caspases, is upregulated and activated just prior to mitosis. Pretreatment of human hepatoma cells with a caspase 3 inhibitor z-DEVD-FMK, prior to the treatment with an antimicrotubule drug nocodazole, abrogates the mitotic arrest, suggesting that caspase 3 (or a caspase 3-like enzyme) might be involved in mitotic-spindle checkpoint. The studies not only characterize caspase 3 as a cell cycle-regulated protein, but also link the protein to nocodazole-dependent mitotic checkpoint, greatly expanding the understanding of caspase 3.