RESUMEN
STUDY DESIGN: a genetic association study was performed on 126 patients with adolescent idiopathic scoliosis and 197 healthy controls from independent Hungarian pedigrees. OBJECTIVE: to reveal implication of promoter polymorphisms of bone morphogenetic protein 4 (BMP4), interleukin-6 (IL6), leptin, matrix metalloproteinase-3 (MMP3), melatonin 1B receptor (MTNR1B) genes in adolescent idiopathic scoliosis (AIS). Combinatorial association of these candidate genes was also studied to detect additive effect of certain single-nucleotide polymorphism (SNP) patterns. SUMMARY OF BACKGROUND DATA: it was previously unraveled that IL6, MMP3, and MTNR1B genes could be considered as predisposition genes of AIS. Since BMP4 and leptin play a central role in bone formation and remodeling and are in direct interaction with melatonin, IL6, and MMP3, these also can be potential predisposition genes. METHODS: the genotyping was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: at a single gene level, no significant differences were found for allele and genotype frequencies of the polymorphisms of these genes between cases or controls; therefore, the formerly detected association of IL6, MMP3, and MTNR1B with AIS was not confirmed in the Hungarian population by independent SNP analysis. However, significantly increased AIS risk was observed at particular combinations of genotypes of paired SNPs of the candidate genes. CONCLUSIONS: the genetic effect of promoter polymorphisms of BMP4, IL6, leptin, MMP3, and MTNR1B can be synergistic for susceptibility to AIS. The combinatorial effect can modulate the final biological impact of many susceptibility polymorphisms; therefore, this should be considered at the comparison of results from case-control studies of different populations.
Asunto(s)
Proteína Morfogenética Ósea 4/genética , Interleucina-6/genética , Leptina/genética , Metaloproteinasa 3 de la Matriz/genética , Polimorfismo de Nucleótido Simple , Receptor de Melatonina MT2/genética , Escoliosis/genética , Adolescente , Femenino , Frecuencia de los Genes , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Modelos Genéticos , Regiones Promotoras Genéticas/genética , Adulto JovenRESUMEN
The regulation of growth cone actin dynamics is a critical aspect of axonal growth control. Among the proteins that are directly involved in the regulation of actin dynamics, actin nucleation factors play a pivotal role by promoting the formation of novel actin filaments. However, the essential nucleation factors in developing neurons have so far not been clearly identified. Here, we show expression data, and use true loss-of-function analysis and targeted expression of activated constructs to demonstrate that the Drosophila formin DAAM plays a critical role in axonal morphogenesis. In agreement with this finding, we show that dDAAM is required for filopodia formation at axonal growth cones. Our genetic interaction, immunoprecipitation and protein localization studies argue that dDAAM acts in concert with Rac GTPases, Profilin and Enabled during axonal growth regulation. We also show that mouse Daam1 rescues the CNS defects observed in dDAAM mutant flies to a high degree, and vice versa, that Drosophila DAAM induces the formation of neurite-like protrusions when expressed in mouse P19 cells, strongly suggesting that the function of DAAM in developing neurons has been conserved during evolution.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Sistema Nervioso Central/embriología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriología , Conos de Crecimiento/metabolismo , Neurogénesis/genética , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestructura , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Línea Celular , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Secuencia Conservada/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Evolución Molecular , Femenino , Conos de Crecimiento/ultraestructura , Masculino , Ratones , Mutación/genética , Vías Nerviosas/citología , Vías Nerviosas/embriología , Vías Nerviosas/metabolismo , Neuritas/metabolismo , Neuritas/ultraestructura , Profilinas/metabolismo , Proteínas de Unión al GTP rac/metabolismoRESUMEN
The aim of the present study was to investigate the oxidative status of lymphocytes from children (n=7) and adults (n=18) with Down's syndrome (DS). The basal oxidative condition, the vulnerability to in vitro hydrogen peroxide exposure, and the repair capacity were measured by means of the damage-specific alkaline comet assay. Significantly and age-independently elevated numbers of single strand breaks and oxidized bases (pyrimidines and purines) were found in the nuclear DNA of the lymphocytes in the DS group in the basal condition. These results may support the role of an increased level of endogenous oxidative stress in DS and are similar to those previously demonstrated in Alzheimer's disease. In the in vitro oxidative stress-induced state, a markedly higher extent of DNA damage was observed in DS children as compared with age- and gender-matched healthy controls, suggesting that young trisomic lymphocytes are more sensitive to oxidative stress than normal ones. However, the repair ability itself was not found to be deteriorated in either DS children or DS adults.