RESUMEN
Vitamin K-dependent carboxylase catalyzes the posttranslational modification of glutamate to gamma-carboxyglutamate (Gla) in its substrates, the vitamin K-dependent proteins (VKDPs). This modification is required for the activities of the VKDPs. Recent evidence demonstrates previously unrecognized roles for VKDPs as signaling molecules important in the regulation of cell growth, adhesion, and apoptosis, suggesting developmental functions for VKDPs and hence the carboxylase. The tissue distribution and functions of carboxylase in development are unknown. In this study, we isolated and characterized the full-length cDNA encoding the rat carboxylase and analyzed, at the cellular level, the expression of this gene in rat embryos by in situ hybridization. We demonstrate that the expression of this gene is highly regulated in a developmental and tissue-specific manner. Hepatocytes, the major site of synthesis of VKDPs of blood coagulation, express carboxylase mRNA late in gestation, in contrast to the central nervous system, mesenchymal, and skeletal tissues which express carboxylase mRNA early during rat embryogenesis. The tissue-specific temporal expression of the carboxylase gene during embryogenesis indicates that vitamin K-dependent carboxylation and the formation of Gla is developmentally regulated. These studies suggest that vitamin K-dependent carboxylation is an important modulator of embryonic VKDP function.
Asunto(s)
Ligasas de Carbono-Carbono/genética , Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Ligasas de Carbono-Carbono/metabolismo , Bovinos , Clonación Molecular , ADN Complementario , Desarrollo Embrionario/genética , Femenino , Humanos , Datos de Secuencia Molecular , Embarazo , Ratas , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Distribución TisularAsunto(s)
Tamización de Portadores Genéticos , Globinas/análisis , Globinas/genética , Eliminación de Secuencia , Talasemia alfa/diagnóstico , Humanos , Reacción en Cadena de la Polimerasa/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Talasemia alfa/sangre , Talasemia alfa/genéticaRESUMEN
We present 20 patients in whom drug therapy was associated with interstitial histiocytic infiltrates with variable degeneration of collagen and elastic fibers mimicking early lesions of granuloma annulare (GA). Most patients had a reproducible clinical presentation comprising erythematous-to-violaceous, nonpruritic plaques, often with an annular pattern, predominantly involving inner aspects of the arms, medial thighs and intertriginous areas. The most frequent clinical differential diagnoses included cutaneous T cell lymphoma, erythema annulare centrifigum (EAC), GA, and lupus erythematosus. A drug reaction was suspected in only 3 cases. The implicated drug classes included calcium channel blockers, angiotensin converting enzyme inhibitors, beta-blockers, lipid-lowering agents, antihistamines, anticonvulsants and antidepressants. Patients were often on two or more of these drugs; all have been associated with pseudolymphomatous infiltrates of the skin, the presumptive basis of which is iatrogenic pertubation of immune function. The defining histomorphology was diffuse infiltration of the interstitium by lymphocytes and histiocytes with piecemeal fragmentation of collagen and elastic fibers in concert with a vacuolar interface dermatitis. Ten cases showed intermediate and transformed lymphocytes with hyperchromatic convoluted nuclei disposed interstitially within the dermis or along the dermoepiderma junction with variable epidermotropism. In the 15 patients who discontinued the implicated drug, lesional resolution occurred. We propose the designations interstitial granulomatous drug reaction for this novel cutaneous reaction pattern.