Genetic drivers of kidney defects in the digeorge syndrome

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P = 4.5×1014). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-Altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver

Perfil eletroforético das proteínas séricas de frangos de corte alimentados com dietas contendo aflatoxinas e/ou argila clinoptilolita natural Electrophoresis profile of serum proteins in broilers fed with diets containing aflatoxins and/or natural clinoptilolite clay

O objetivo do presente trabalho foi avaliar o perfil eletroforético das proteínas séricas de frangos de corte alimentados com dietas contendo aflatoxinas e/ou argila clinoptilolita natural. Foram utilizados 528 frangos de corte, machos, da linhagem Ross, distribuídos em seis tratamentos com 4 repetições cada: T1 - testemunha (ração sem aflatoxinas ou clinoptilolita), T2 - ração com 5ppm de aflatoxinas, T3 - ração com 0,25% de clinoptilolita, T4 - ração com 5ppm de aflatoxinas e 0,25% de clinoptilolita, T5 - ração com 0,5% de clinoptilolita e T6 - ração com 5ppm de aflatoxinas e 0,5% de clinoptilolita. Os animais ficaram alojados em 24 boxes, e submetidos aos tratamentos do 1&deg; ao 42&deg; dia, quando foram sacrificados. Foram analisadas as proteínas totais, as frações albumina, alfa 1, alfa 2, beta e gama. Com exceção das médias da fração gama, o teste de Tukey revelou diferenças significativas (P<0,05) nas médias de todas as proteínas totais e frações protéicas nos tratamentos onde as aflatoxinas estavam presentes. A ação das aflatoxinas nas proteínas totais ocorre na síntese de albumina e globulinas (frações alfa e beta). As gamaglobulinas não são afetadas pelas aflatoxinas. Em relação ao controle, as aves alimentadas com dietas com aflatoxinas e clinoptilolita apresentaram baixos (P<0,05) níveis de proteína total, albumina e globulinas (alfa e beta). Conclui-se que as aflatoxinas alteram o perfil eletroforético e que a clinoptilolita adicionada na ração não é capaz de evitar essas alterações.<br>This study was aimed at evaluating the electrophoresis profile of serum protein in broilers fed with diets containing aflatoxins and natural clinoptilolite clay. Five hundred and twenty eight male broilers Ross were distributed in six treatments and each one with 4 replications: T1 - control (without aflatoxins or clinoptilolite), T2 -5ppm of aflatoxins, T3 -0.25% of clinoptilolite, T4 -5ppm of aflatoxins and 0.25% of clinoptilolite, T5 -0.5% of clinoptilolite and T6 - 5ppm of aflatoxins and 0.5% of clinoptilolite. The broilers were allocated in 24 boxes and submitted to a treatments for 42 days, when they were slaughtered. Total proteins, albumin fractions, alpha 1, alpha 2, beta and gamma were analyzed. Except gamma fraction the Tukey test showed differences (P<0.05) on serum total proteins and proteins fractions in all treatments which aflatoxin was present. The clinoptilolite did not modify (P<0.05) the serum proteins. The control broilers fed with diets containing aflatoxins and clinoptilolite presented low levels (P<0.05) of total protein, albumin, and globulins (alpha and beta fractions). In conclusion, aflatoxins change the electrophoresis profile and clinoptilolite is not able to protect avoid these changes