Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux

Abstract Vesicoureteric reflux (VUR) is the commonest urological anomaly in children. Despite treatment improvements, associated renal lesions – congenital dysplasia, acquired scarring or both – are a common cause of childhood hypertension and renal failure. Primary VUR is familial, with transmission rate and sibling risk both approaching 50%, and appears highly genetically heterogeneous. It is often associated with other developmental anomalies of the urinary tract, emphasising its etiology as a disorder of urogenital tract development. We conducted a genome-wide linkage and association study in three European populations to search for loci predisposing to VUR. Family-based association analysis of 1098 parent-affected-child trios and case/control association analysis of 1147 cases and 3789 controls did not reveal any compelling associations, but parametric linkage analysis of 460 families (1062 affected individuals) under a dominant model identified a single region, on 10q26, that showed strong linkage (HLOD = 4.90; ZLRLOD = 4.39) to VUR. The ~9Mb region contains 69 genes, including some good biological candidates. Resequencing this region in selected individuals did not clearly implicate any gene but FOXI2, FANK1 and GLRX3 remain candidates for further investigation. This, the largest genetic study of VUR to date, highlights the 10q26 region as a major genetic contributor to VUR in European populations

A Genetic Basis of Susceptibility to Acute Pyelonephritis

For unknown reasons, urinary tract infections (UTIs) are clustered in certain individuals. Here we propose a novel, genetically determined cause of susceptibility to acute pyelonephritis, which is the most severe form of UTI. The IL-8 receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage.We have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of 23% and 25% compared to 7% in controls (p<0.001 and p<0.0001, respectively). When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription.The results identify a genetic innate immune deficiency, with a strong link to APN and renal scarring

FAT1 mutations cause a glomerulotubular nephropathy

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function

An eco-zonal assessment of eight mulberry varieties in North Central Nigeria

Eight varieties of mulberry plant namely; NG1, K2, S14, S30, S34, S36, S41 and S54 were evaluated at the Ahmadu Bello University farm in Zaria for survival, yield and nutrient contents. The samples of the mulberry plant were collected from the Forestry Research Institute of Nigeria (FRIN) Ibadan. The 8 varieties were planted out using 8 x 8 Latin Square experimental layout. Leaves from these varieties were used separately to feed the domesticated silkworm Bombyx mori L. The study revealed that all the eight varieties could survive in the Northern Guinea Savanna area of the country. The S41 variety had the highest survival rate (78.2%) while S34 variety had the highest leaf yield (28095kg/ha). The performances of varieties S14, S36, NG1 and K2 in terms of leaf yield were low. Leaf analysis revealed that the Nitrogen and Calcium contents of S54 were significantly higher than those of the other seven varieties. This was followed by those of K2, S30 and S34. Sodium content was found to be very high in NG1, S41, S54 and K2. Worms fed with S34 variety produced the highest cocooning percent and also performed well in the production of good cocoons. S54 produced the heaviest single cocoon, the lowest number of cocoons in 1.0kg cocoons, produced cocoons with the least quantity of leaves and its effective rate of rearing determined by the weight of the cocoon produced was superior to others. Variety S54 based on the performances of the silkworms fed with its leaves has therefore been selected for cultivation in the semi arid area of Nigeria. Keywords: Mulberry; Variety; survival; yield; moisture content; chemical content; bombyx mori; cocoonMoor Journal of Agricultural Research Vol. 7 (1&2) 2006 pp. 21-2