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Background: Mutations in podocin (NPHS2) are the most common cause of childhood onset autosomal recessive steroid-resistant nephrotic syndrome (SRNS). The disease is characterized by early-onset proteinuria, resistance to immunosuppressive therapy and rapid progression to end-stage renal disease. Compound heterozygous changes involving the podocin variant R229Q combined with another pathogenic mutation have been associated with a mild phenotype with disease onset often in adulthood. Methods: We screened 19 families with early-onset SRNS for mutations in NPHS2 and WT1 and identified four disease-causing mutations (three in NPHS2 and one in WT1) prior to planned whole-exome sequencing. Results: We describe two families with three individuals presenting in childhood who are compound heterozygous for R229Q and one other pathogenic NPHS2 mutation, either L327F or A297V. One child presented at age 4 years (A297V plus R229Q) and the other two at age 13 (L327F plus R229Q), one with steadily deteriorating renal function. Conclusions: These cases highlight the phenotypic variability associated with the NPHS2 R229Q variant plus pathogenic mutation. Individuals may present with early aggressive disease. [ABSTRACT FROM AUTHOR]

BackgroundEssential hypertension results from the interaction of several genetic and environmental factors. Identification of genetic factors that modulate blood pressure (BP) response to interventions can lead to improved strategies for prevention and control. The purpose of this study was to identify genes that modulate BP response to dietary interventions.MethodsWe used data and samples collected in two randomized feeding studies to determine the extent to which genetic architecture is associated with the effect on BP of sodium intake and the Dietary Approaches to Stop Hypertension (DASH) dietary pattern. Participants in both trials were adults with above-optimal BP or unmedicated stage 1 hypertension. Genomic DNA was typed for several candidate genes.ResultsThe effect of sodium intake on BP differed by genotype at the angiotensinogen, β2-adrenergic receptor, and kallikrein loci. The effect of DASH dietary pattern on BP differed by genotype at the β2-adrenergic receptor locus.ConclusionsThese findings have implications for understanding the mechanism(s) through which diet affects BP, the heterogeneity of these effects, and the extent to which dietary interventions can modulate genetic predisposition.American Journal of Hypertension (2011). doi:10.1038/ajh.2010.223 [ABSTRACT FROM AUTHOR]

Evidence for genetic factors in the development and progression of IgA nephropathy. Background. IgA nephropathy (IgAN) is the most common glomerulonephritis in the world among patients undergoing renal biopsy. Once considered a relatively benign condition, longitudinal follow-up studies have revealed that in fact 9 to 50% of patients progress to end-stage renal disease within 20 years of disease onset. In the three decades since its first description by Jean Berger and Nicole Hinglais, clinical, epidemiologic, and immunologic studies of the pathogenesis of primary (idiopathic) mesangial glomerulonephritis with predominant IgA deposits have characterized the features of IgAN as a distinct glomerular disease entity. However, the basic molecular mechanism(s) underlying abnormal IgA deposition in the mesangium with ensuing extracellular matrix expansion and mesangial cell proliferation remains poorly understood. The task of elucidating the molecular basis of IgAN is made especially challenging by the fact that both environmental and genetic components likely contribute to the development and progression of IgAN. Methods and Results. We review here the evidence for genetic factors in the development and progression of IgAN, including a reappraisal of earlier conflicting results from small immunogenetic case-control studies, the evidence for racial differences in the prevalence of IgAN, a detailed summary of all reported occurrences of familial IgAN worldwide, and an exhaustive review of new insights gained through the study of two murine models of hereditary IgAN: the ddY and the uteroglobin-deficient mouse. Conclusions. With the development of powerful molecular genetic approaches to the study of both Mendelian and complex human genetic diseases, and the successful efforts of investigators to identify and clinically characterize large IgAN multiplex families, we propose that genetic analysis of familial IgAN is the most promising approach to the identification of... [ABSTRACT FROM AUTHOR]

Spectrum of disease in familial focal and segmental glomerulosclerosis. Background. Focal segmental glomerulosclerosis (FSGS) is the underlying pathologic entity in 5% of adults and 20% of children with end-stage renal disease (ESRD). FSGS is generally considered to be sporadic in origin. Methods. Recently, we identified 60 families involving 190 individuals with familial FSGS, providing evidence for a subset of families in which a genetic form is segregating. Each family had at least one member with renal biopsy-confirmed FSGS and at least one other member with either renal biopsy-confirmed FSGS or ESRD. Results. Twenty-six families had individuals affected in more than one generation [multigeneration (MG)], and the remaining 34 families had only a single generation (SG) affected. There was equal representation of males and females among affected individuals. Ten percent of MG families were African American, and 52% of SG families were African American. The mean age of presentation was significantly higher in the MG families (32.5 ± 14.6 years) compared with the SG families (20.1 ± 12.1 years, P = 0.0001). SG cases had higher levels of proteinuria at presentation (7.0 ± 5.6 g/24 hr, compared with 3.8 ± 3.4 g/24 hr, for the MG families, P = 0.002). On renal biopsy, tubulointerstitial damage was more severe in patients in the SG families than in the MG families; however, the level of glomerular damage did not differ between these groups. Fifty percent of the patients had progressed to ESRD by the age of 30 years. Variables measured at presentation that were independently associated with poor renal survival were decreased age, increased serum creatinine, and increased urinary protein excretion. Forty-one patients underwent successful renal transplantation, with a 10-year graft survival rate of 62%. One patient developed clinical and biopsy evidence of recurrence of FSGS in the allograft. Conclusion. These data confirm the existence of a... [ABSTRACT FROM AUTHOR]