RESUMEN
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
LMX1B is a LIM-homeodomain transcription factor required for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Heterozygous loss-of-function mutations in LMX1B cause nail patella syndrome (NPS). To further understand LMX1B gene regulation and to identify pathogenic mutations within the coding region, a detailed analysis of LMX1B gene structure was undertaken. 5' -RACE and primer extension identified a long 5' -untranslated region of 1.3 kb that contains two upstream open-reading frames (uORFs). Transient transfection assays showed that sequences required for basal promoter activity extend no further than 112 bp upstream. An additional 47 mutations have been identified in the coding region, as well as nine deletions of large portions of the gene, but not in the promoter or highly conserved intronic sequences. The range of mutations and the identification of uORFs suggest further complexity in the regulation of LMX1B expression.