The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis Jingyuan Xie et al. # Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1
Nephrotic syndrome (NS) is the most frequent cause of proteinuria in children and is emerging as a leading cause of uremia. Molecular studies in families with recessive NS have led to the discovery of specialized molecules endowed in podocytes that play a role in proteinuria. This review focalizes the key position of podocin (NPHS2 gene) in this rapidly evolving field and furnishes a compendium to those involved in clinics and genetics of NS. Screening for NPHS2 mutations have been done in sporadic NS and familial cases with recessive inheritance, documenting a mutation detection rate of 45-55% in families and 8 -20% in sporadic NS according to the different groups and considering all the clinical phenotypes. Almost 50 NPHS2 mutations have been reported and variants and/or non silent polymorphisms potentially involved in proteinuria were recognized. Personalized data on clinical aspects related to responsiveness to drugs, evolution to end stage renal failure and post-transplant outcome are reported. Functional studies and cell sorting experiments demonstrated retention in the endoplasmic reticulum of most mutants involving the stomatin domain. Pull-down experiments with the common R229Q polymorphism demonstrated an altered interaction with nephrin that affects the stability of the functional unit. Overall, data are here presented that underscore a major role of inherited defects of NPHS2 in NS in children (including a relevant impact in sporadic cases) and give the functional rationale for the association. A practical compendium is also given to clinicians involved in the management of NS that should modify the classic therapeutic approach. Nephrotic syndrome (NS) is the most frequent glomerular disease in children (1) and the pathologic variant with focal segmental glomerulosclerosis is emerging as a leading cause of end stage renal failure. The annual incidence in children has been estimated to be 2.0 to 2.7 per 100.000 in USA with a cumulative prevalence of 16 per 100.000. Geographic or ethnic differences have been reported with a 6-fold greater incidence in Asian than in European children (2,3). It appears to be a clinical heterogeneous condition characterized by histologic variants (4 -6) and different genetic backgrounds (7-9) with recessive and dominant inheritances. In the last few years, advances in molecular genetics of familial NS have led to the discovery of specialized molecules endowed in podocytes as responsible for proteinuria. They also have clearly indicated that the podocyte is the prevailing glomerular site for repulsion of proteins, a process that allows maintenance of big molecules (such as proteins with a molecular weight Ͼ 40 kilo Dalton) in the vascular bed and ultra-filtration of water and solutes. Podocytes are specialized epithelia with a cell body and several polipoid cellular extra-flections that cover the outer surface of glomerular basement membrane. The inter-podocyte connection, called slit-diaphragm, is reminiscent of a tight junction with differentiated structure and functions...
Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.
Introduction Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD- UMOD ) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD- UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. Methods An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). Results The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected ( P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. Conclusion We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD.
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