RESUMEN
BACKGROUND: Very little is known about the identity of genetic factors involved in the complex etiology of nonsyndromic neural tube defects (NTD). Potential susceptibility genes have emerged from the vast number of mutant mouse strains displaying NTD. Reasonable candidates are the human homologues of mice exencephaly genes Tfap2alpha and Msx2, which are expressed in the developing neural tube. METHODS: A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2alpha and MSX2 was performed for 204 nonsyndromic NTD patients including cases of anencephaly (n = 10), encephalocele (n = 8), and spina bifida aperta, SBA (n = 183). A selected number of SBA patients was additionally tested for specific mutations in MTHFD, FRalpha, and PAX1 already shown to be related to NTD. RESULTS: Two TFAP2alpha point mutations in individual SBA patients were silent on the amino acid level (C308C, T396T). On nucleic acid level, these mutations change evolutionary conserved codons and thus may influence mRNA processing and translation efficiency. One SBA patient displayed an exonic 9-bp deletion in MSX2 leading to a shortened and possibly less functional protein. None of these mutations was found in 222 controls. Seven polymorphisms detected in TFAP2alpha and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2alpha polymorphism were at a slightly increased risk of NTD (OR 1.71; 95% CI 0.57-5.39). CONCLUSIONS: Although several new genetic variants were found in TFAP2 and MSX2, no statistically significant association was found between NTD cases and the new alleles or their combinations. Further studies are necessary to finally decide if these gene variants may have acted as susceptibility factors in our individual cases.
Asunto(s)
Proteínas de Unión al ADN/genética , Mutación , Defectos del Tubo Neural/genética , Receptores de Superficie Celular , Factores de Transcripción/genética , Alelos , Anencefalia/genética , Animales , Secuencia de Bases , Proteínas Portadoras/genética , Codón , ADN Complementario/metabolismo , Encefalocele/genética , Exones , Receptores de Folato Anclados a GPI , Ácido Fólico/metabolismo , Eliminación de Gen , Genotipo , Proteínas de Homeodominio , Humanos , Ratones , Datos de Secuencia Molecular , Linaje , Mutación Puntual , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , Disrafia Espinal/genética , Factor de Transcripción AP-2RESUMEN
Aqueous-ethanolic extracts of Fraxinus excelsior, Populus, tremula and Solidago virgaurea in a combination of 1: 3: 1 (v/v/v) are the components of the plant drug Phytodolor N (abbreviated as PD), which exhibits antipyretic, analgesic and antirheumatic activity. Similar to a broad variety of synthetic non-steroidal anti-inflammatories the mentioned plant extracts inhibit dihydrofolate reductase. The following concentrations as percentage in the test volumes represent the individual I50-values: F. excelsior = 0.26% (v/v); P. tremula = 0.46% (v/v) and S. virgaurea = 0.6% (v/v). The combined extracts in PD exhibit an I50 at 0.3% (v/v). Testing the activity of the water-soluble compounds of corresponding dry extracts, the activity of F. excelsior with an apparent I50-value of 0.008% (w/v) by far dominates the inhibitory overall effect of the combination (I50 = 0.014%, w/v).