RESUMEN
BACKGROUND: Myo-inositol, glucose and zinc and related genetic factors are suggested to be implicated in the etiology of spina bifida. We investigated the biochemical concentrations of these nutrients and polymorphisms in the myo-inositol transporter SLC5A11, myo-inositol synthase ISYNA1, and zinc transporter SLC39A4 in association with spina bifida risk. METHODS: Seventy-six spina bifida triads only were ascertained. In mothers, fathers, and spina bifida children polymorphisms determined were SLC5A11 (544C > T), ISYNA1 (1029A > G), and SLC39A4 (1069C > T). Serum myo-inositol and glucose, and red blood cell zinc concentrations were determined in mothers and spina bifida children. Transmission disequilibrium tests (TDT) were applied to determine associations between the polymorphisms and spina bifida. Associations between biochemical values and genotypes were studied by one-way analysis of variance (ANOVA). Interactions between alleles, biochemical values, and environmental factors were analyzed by conditional logistic regression. RESULTS: No association between SLC5A11, ISYNA1, and SLC39A4 and spina bifida was shown, chi2SLC5A11=0.016, P=0.90; chi2SYNA1=1.52, P=0.22; chi2SLC39A4=0.016, P=0.90; and degrees of freedom (df)=1. Maternal glucose concentrations were comparable for the SLC5A11 genotypes. Significantly lower myo-inositol concentrations were observed in mothers with SLC5A11 CC-genotype, mean (SD) 14.2 (2.6)micromol/L compared to SLC5A11 TT-genotype, 17.0 (3.4)micromol/L, P <0.05 . No significant associations were observed between ISYNA1 and myo-inositol and glucose, and between SLC39A4 and zinc. A significant interaction was demonstrated between a maternal glucose < 4.5 mmol/L and ISYNA1 1029A > G polymorphism on spina bifida risk. CONCLUSION: The combination of maternal glucose < 4.5 mmol/L and ISYNA1 1029A > G polymorphism protects against spina bifida offspring. Moreover, maternal SLC5A11 544C > T polymorphism contributes to the serum myo-inositol concentration. Larger studies should confirm these findings.
Asunto(s)
Glucemia/metabolismo , Inositol/sangre , Disrafia Espinal/genética , Zinc/metabolismo , Consumo de Bebidas Alcohólicas , Índice de Masa Corporal , Estudios de Casos y Controles , Preescolar , Eritrocitos/metabolismo , Femenino , Humanos , Lactante , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Oportunidad Relativa , Polimorfismo Genético , Disrafia Espinal/metabolismoAsunto(s)
Proteínas de Unión al ADN/genética , Proteínas de la Membrana/genética , Defectos del Tubo Neural/genética , Proteínas Tirosina Quinasas/genética , Factores de Transcripción/genética , Proteína Tirosina Quinasa CSK , Proteínas de Unión a Calmodulina , ADN/química , ADN/genética , Análisis Mutacional de ADN , ADN Complementario/química , ADN Complementario/genética , Frecuencia de los Genes , Genotipo , Humanos , Proteínas de Microfilamentos , Modelos Genéticos , Mutación , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , Eliminación de Secuencia , Factor de Transcripción AP-2 , Familia-src QuinasasRESUMEN
Bent tail is a mouse model for human neural tube defects. Bent tail mice are characterized by a shortened, kinked tail. We have observed numerous aberrations in Bent tail embryos including exencephaly, rotation defects and occasionally omphalocele, orofacial schisis and situs abnormalities. Exencephaly was seen in >10% of all embryos and resulted from a closure defect of the hindbrain. Bent tail maps to the proximal part of the X chromosome. By haplotype analysis we have appointed the Bent tail locus to a 1.1 cM interval between markers DXMit159 and DXMit143. Subsequent analysis has revealed the presence of a deletion in all affected animals. The deletion is approximately 1 Mb in size and encompasses the gene for ZIC:3, a zinc finger transcription factor expressed in murine neuroectoderm and dorsal axial mesoderm during neurulation. ZIC:3 is a homolog of the Drosophila segmentation gene odd-paired. Although the Bent tail phenotype probably is the result of the deletion of several genes, combining data on ZIC:3 expression and function of ZIC: genes in the mouse shows that deletion of Zic3 alone is compatible with a major role of this gene in the congenital malformations of the Bent tail mouse. In man, mutations in ZIC3 are associated with situs abnormalities. These patients occasionally also show spina bifida, indicating that genetic variation in human ZIC3 may contribute to other congenital malformations, including neural tube defects.
Asunto(s)
Proteínas de Homeodominio/genética , Defectos del Tubo Neural/genética , Cola (estructura animal)/anomalías , Factores de Transcripción/genética , Cromosoma X/genética , Animales , Mapeo Cromosómico , ADN/genética , Modelos Animales de Enfermedad , Embrión de Mamíferos/anomalías , Embrión de Mamíferos/metabolismo , Femenino , Eliminación de Gen , Ligamiento Genético , Factores de Intercambio de Guanina Nucleótido , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Endogámicos , Fenotipo , Proteínas Proto-Oncogénicas/genética , Cola (estructura animal)/embriologíaRESUMEN
The cDNA coding sequence of the Agaricus bisporus hydrophobin gene ABH1 under the regulation sequences of the Schizophyllum commune SC3 hydrophobin gene gave no expression in S. commune. In contrast, the genomic coding sequence (containing three introns) produced high levels of ABH1 mRNA when transformed to S. commune in the same configuration. Apparently, introns were needed for the accumulation of mRNAs from the ABH1 gene. When the effect of intron deletion on expression of the homologous genes SC3 and SC6 was examined, it was observed that only the genomic coding sequences were expressed in S. commune. Run-on analysis with nuclei harbouring intron-containing and intronless SC6 showed that this effect did not occur at the level of transcription initiation: genomic and cDNA sequences were equally active in this respect. When a 50 bp artificial intron containing the consensus splice and branch sites of S. commune introns, in addition to random-generated sequences, was introduced in the right orientation into the intronless SC3 transcriptional unit, accumulation of SC3 mRNA was restored. By polymerase chain reaction amplification, no unspliced SC3 mRNA species could be detected. Furthermore, the addition of an intron into the transcriptional unit of the gene for green fluorescent protein (GFP) effected clear fluorescence of the transgenic hyphae. Apparently, splicing is required for the normal processing of primary transcripts in S. commune.
