RESUMEN
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene. DGAT2 encodes an endoplasmic reticulum-mitochondrial-associated membrane protein, acyl-CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and overexpression of the mutant DGAT2 significantly inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal-dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies.
Asunto(s)
Axones/patología , Enfermedad de Charcot-Marie-Tooth/genética , Diacilglicerol O-Acetiltransferasa/genética , Diacilglicerol O-Acetiltransferasa/metabolismo , Mutación Missense , Adulto , Edad de Inicio , Animales , Axones/metabolismo , Línea Celular , Proliferación Celular , Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones , Neuronas Motoras/citología , Neuronas Motoras/metabolismo , Linaje , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
INTRODUCTION: The lysosomal cysteine protease cathepsin B is known to play an important role in the resolution of organic matrix, a final step in bone resorption. Cystatins function as an inhibitor of cathepsin B. Determining the correlation between cathepsin B and cystatin levels in gingival crevicular fluid at various times might provide a better understanding of both the dynamics and the metabolic stages of orthodontic tooth movement. METHODS: Human gingival crevicular fluid was collected at the distal sulcus from the canines of persons not in orthodontic treatment, in retention, and in retraction at various times (initial, 1 day, 1 week, and 1 month postretraction). Cathepsin B and its inhibitor, cystatin, were found with fluorometry. RESULTS: The level of cathepsin B was varied in the retraction group; this was different from the retention and the nonorthodontic groups. Significant initial decreases after force application and subsequent increases by 1 month posttreatment were observed in the retraction group. The variations and differences among groups were negatively correlated with cystatin. CONCLUSIONS: The balance between enzyme and inhibitor might reflect the clinical status of orthodontic tooth movement and provide valuable information for the assessment of recall intervals and retention procedures.