Primary vesicoureteral reflux (VUR) is the most common urological anomaly in children, affecting 1-2% of the pediatric population and 30-40% of children presenting with urinary tract infections (UTIs). Reflux- associated nephropathy is a major cause of childhood hypertension and chronic renal failure. The hereditary and familial nature of VUR is well recognized and several studies have reported that siblings of children with VUR have a higher incidence of reflux than the general pediatric population. Familial clustering of VUR implies that genetic factors have an important role in its pathogenesis, but no single major locus or gene for VUR has yet been identified and most researchers now acknowledge that VUR is genetically heterogeneous. Improvements in genome-scan techniques and continuously increasing knowledge of the genetic basis of VUR should help us to further understand its pathogenesis.
Summary 86% of immunoglobulin G (IgG) heavy‐chain gene transcripts were found to be non‐functional in the peripheral blood B cells of a patient initially diagnosed with common variable immunodeficiency, who later developed raised IgM, whereas no non‐functionally rearranged transcripts were found in the cells of seven healthy control subjects. All the patient's IgM heavy‐chain and κ light‐chain transcripts were functional, suggesting that either non‐functional rearrangements were being selectively class‐switched to IgG, or that receptor editing was rendering genes non‐functional after class‐switching. The functional γ‐chain sequences showed a normal rate of somatic hypermutation while non‐functional sequences contained few somatic mutations, suggesting that most came from cells that had no functional gene and therefore were not receiving signals for hypermutation. However, apoptosis of peripheral blood lymphocytes was not impaired. No defects have been found in any of the genes currently known to be responsible for hyper‐IgM syndrome but the phenotype fits best to type 4.
Serum cholinesterase is an enzyme similar to acetylcholinesterase but of unknown function. Activity varies widely between individuals and numerous variants are known. Numerous studies have related the activity of serum cholinesterase to serum lipid concentrations but it is not known whether the enzyme plays a part in lipoprotein metabolism nor, if it does, whether this is related to its catalytic activity or to some other feature of the protein. It was therefore decided to compare the relationships of its concentration and activity to the concentrations of serum lipids and lipoproteins. -- Cholinesterase was purified from human serum, and antiserum was raised in a rabbit. The antiserum was used to measure the concentration of the enzyme by radial immunodiffusion in sera from 117 blood donors and 282 patients for whom serum lipid profiles had been requested. -- In the donor group the correlation between activity and concentration of the enzyme was 0.95 and there was little difference between the correlations of the two measures of cholinesterase with lipids. In the patient group the correlation between serum cholinesterase activity and concentration was only 0.88 and all the lipid indices correlated better with the concentration of cholinesterase than with activity. This was probably because of variable loss of activity during transport and storage, and because of enzyme inhibition by drugs. -- For further analysis the patients were preferred because they had fasted before blood sampling and had a greater range of lipid concentrations. Correlations with cholinesterase concentration were in the order 'total LDL' (LDL + VLDL) > VLDL > triacylglycerols > cholesterol. The correlation coefficients were similar, 0.51 with 'total LDL' as against 0.41 with cholesterol, but the shapes of the plots were markedly different. The plot of cholinesterase against cholesterol showed very weak relationship. The plot against triacylglycerols showed a well-defined triangular shape. At lower triacylglycerol concentrations a wide range of cholinesterase concentrations was found but with high triacylglycerol concentrations the enzyme concentration was always high. The possible nature of the relationship is discussed. -- In the preparatory stages, impurities occurring in affinity-purified cholinesterase were investigated by western blotting; and in concentration measurement, reproducible variation in precipitin ring patterns between individuals was observed. -- Key words: Serum cholinesterase concentration; serum lipids; immunological variation of serum cholinesterase.
The p.Gly691Ser variant of the RET protein, resulting from the 'A' allele of the SNP rs1799939 in exon 11 of the RET gene, was recently found to be present in a high proportion of primary vesicoureteric reflux (pVUR) patients in Quebec. We have determined the genotype of this SNP in 221 unrelated index cases of pVUR from the Irish population, in 190 full siblings of 160 of the index cases, and in 592 healthy controls. We found no significant difference in genotype or allele frequencies in patients and controls, and no tendency of affected siblings to share the same genotype. We also found no difference in the presence of additional phenotypic features such as duplex kidneys, between patients with and without the 'A' allele, and no difference in grade of reflux. We find no evidence of any influence of RET SNP rs1799939 on pVUR phenotype.
Significance Statement Vesicoureteral reflux (VUR) is associated with progressive kidney disease. Familial aggregation supports a hereditary basis; however, its genetic architecture remains to be elucidated. The largest VUR copy number variant analysis and genome-wide association study to date accounts for multiple modes of inheritance and sex-specific effects in VUR, identifying three study-wide significant and five suggestive loci with large effects, containing canonical developmental genes including WDPCP and WNT5A . Results of experiments in mice support novel roles of Wnt5a in urogenital development. Altogether, 6% of patients carried high-risk genotypes. These findings have important implications for VUR screening. Background Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. Methods A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. Results Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P =6.35×10 −8 ) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41–6.9), containing canonical developmental genes expressed in the developing urinary tract ( WDPCP, OTX1, BMP5, VANGL1, and WNT5A ). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P =1.86×10 –9 ). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. Conclusions These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.
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