Asunto(s)
Anomalías Múltiples/diagnóstico , Trastornos Relacionados con Cocaína/complicaciones , Síndrome de la Uña-Rótula/diagnóstico , Complicaciones del Embarazo/etiología , Anomalías Múltiples/etiología , Ano Imperforado/diagnóstico , Ano Imperforado/embriología , Femenino , Estudios de Seguimiento , Hernia Umbilical/diagnóstico , Hernia Umbilical/embriología , Humanos , Recién Nacido , Exposición Materna/efectos adversos , Síndrome de la Uña-Rótula/embriología , Embarazo , Complicaciones del Embarazo/diagnóstico , Primer Trimestre del Embarazo , Segundo Trimestre del Embarazo , Enfermedades Raras , Medición de Riesgo , Escoliosis/diagnóstico , Escoliosis/embriología , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/embriologíaRESUMEN
Nail patella syndrome (NPS) is an autosomal dominant disorder affecting development of the limb, kidney and eye. NPS is the result of heterozygous loss-of-function mutations in the LIM-homeodomain transcription factor, LMX1B. Recent studies suggest that the NPS phenotype may be more extensive than recognized previously including neurologic and neurobehavioral aspects. To determine whether these findings correlated with the expression of Lmx1b during development, an internal ribosomal entry site-LacZ reporter was inserted into the 3'UTR of the endogenous murine gene. The pattern of Lmx1b expression during the development of the limb, eye and kidney correlates with the NPS phenotype. Additional sites of expression were observed in the central nervous system (CNS). The effects of the absence of Lmx1b in the CNS were determined in lmx1b-/- mice by histology and immunocytochemistry. Lmx1b is required for the differentiation and migration of neurons within the dorsal spinal cord. The inability of afferent sensory neurons to migrate into the dorsal horn is entirely consistent with diminished pain responses in NPS patients.
Asunto(s)
Sistema Nervioso Central/embriología , Proteínas de Homeodominio/biosíntesis , Síndrome de la Uña-Rótula/genética , Factores de Transcripción/biosíntesis , Animales , Enfermedades del Sistema Nervioso Central/embriología , Enfermedades del Sistema Nervioso Central/genética , Modelos Animales de Enfermedad , Femenino , Proteínas de Homeodominio/genética , Humanos , Riñón/anomalías , Riñón/embriología , Proteínas con Homeodominio LIM , Deformidades Congénitas de las Extremidades/embriología , Deformidades Congénitas de las Extremidades/genética , Masculino , Ratones , Ratones Mutantes , Síndrome de la Uña-Rótula/embriología , Neuronas Aferentes/fisiología , Fenotipo , Factores de Transcripción/genéticaRESUMEN
Nail changes may be marker lesions for complex systemic disorders and herald associated syndromes. Knowledge of the anatomy, embryology and biochemical properties of the nail apparatus is essential for understanding the pathogenesis of hereditary nail disorders. In the last few years significant progress has been made in the field of clinical and molecular pathology of human diseases. A considerable number of the genes responsible for genodermatoses have been identified. The homeobox master control genes, genes encoding for transcription factors, genes encoding for the maintenance of telomeres, or for structural molecules, such as the similarly evolutionary highly conserved a-helical rod domains of keratins, are involved in the embryogenesis and normal functioning of nails. Using nail changes in selected genodermatoses with a known genetic background, we try to elucidate the genesis of inherited nail disorders and review the resultant clinical manifestations.
Asunto(s)
Anomalías Múltiples , Enfermedades de la Uña , Uñas/anatomía & histología , Enfermedades Cutáneas Genéticas , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Disqueratosis Congénita/embriología , Disqueratosis Congénita/genética , Humanos , Enfermedades de la Uña/congénito , Enfermedades de la Uña/genética , Enfermedades de la Uña/patología , Síndrome de la Uña-Rótula/embriología , Síndrome de la Uña-Rótula/genética , Uñas/embriología , Uñas/fisiología , Síndrome de Rubinstein-Taybi/embriología , Síndrome de Rubinstein-Taybi/genética , Enfermedades Cutáneas Genéticas/patologíaRESUMEN
Proper development of the anterior segment of the mammalian eye is critical for normal ocular function. Indeed, several congenital syndromes associated with anterior segment anomalies can lead to impaired vision and glaucoma. One such syndrome is nail patella syndrome (NPS), caused by haploinsufficiency for the LIM-homeodomain transcription factor LMX1B. Although mutations in LMX1B cosegregate with NPS, whether these mutations cause the glaucoma associated with NPS is not known. Here, we provide evidence that the LIM-homeodomain transcription factor lmx1b is an essential regulator of murine anterior segment development. Mice that are homozygous for a targeted mutation of lmx1b display iris and ciliary body hypoplasia, and cornea stromal defects. In addition, two cDNAs normally downregulated in presumptive cornea, mf1 and mfh1, exhibit persistent expression, while keratocan, a keratin sulfate proteoglycan expressed by keratocytes, is not detected in mutant corneas. Moreover, ultrastructural examination of homozygous mutants indicates that corneal collagen fibrillogenesis is perturbed. Taken together, our studies suggest a developmental etiology for glaucoma in NPS patients and highlight lmx1b as an essential regulator of anterior segment morphogenesis and patterning. genesis 26:15-25, 2000.
Asunto(s)
Segmento Anterior del Ojo/embriología , Proteínas del Ojo/fisiología , Regulación del Desarrollo de la Expresión Génica , Genes Homeobox , Glaucoma/genética , Proteínas de Homeodominio/fisiología , Síndrome de la Uña-Rótula/genética , Animales , Animales Recién Nacidos , Segmento Anterior del Ojo/crecimiento & desarrollo , Segmento Anterior del Ojo/patología , Cuerpo Ciliar/anomalías , Cuerpo Ciliar/embriología , Cuerpo Ciliar/patología , Colágeno/metabolismo , Colágeno/ultraestructura , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Proteínas del Ojo/biosíntesis , Proteínas del Ojo/genética , Proteínas Fetales/biosíntesis , Proteínas Fetales/genética , Proteínas Fetales/fisiología , Glaucoma/metabolismo , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/genética , Hibridación in Situ , Iris/anomalías , Iris/embriología , Iris/patología , Proteínas con Homeodominio LIM , Mesodermo/metabolismo , Ratones , Ratones Noqueados , Microscopía Electrónica , Morfogénesis , Síndrome de la Uña-Rótula/embriología , Síndrome de la Uña-Rótula/patología , Proteoglicanos/biosíntesis , Proteoglicanos/genética , Células del Estroma/patología , Factores de TranscripciónRESUMEN
Nail-patella syndrome (NPS), hereditary onycho-osteodysplasia, is an autosomal dominant disorder of nail dystrophy, patellar absence or hypoplasia, incomplete elbow extension, conical posterior iliac horns, and nephropathy. We studied the kidneys of an 18-week spontaneously aborted fetus of a mother with the NPS. Ultrastructural examination of the kidney showed thickening of the capillary walls of the glomeruli and mesangium. There was irregular thickening of basement membranes with subendothelial fibrillar electron-dense deposits. Immunofluorescence showed fibrinogen deposition in glomerular basement membranes. Fibrinogen deposition in utero may ultimately lead to glomerular fibrosis and intrabasement membrane collagen deposition as seen in the adult renal lesion of this syndrome. This is the first report of the NPS in which the renal abnormalities have been studied in a fetus. These findings provide support for possible prenatal diagnosis of NPS by intra-uterine kidney biopsy.