Congenital nephrotic syndrome (NPHS1): Features resulting from different mutations in Finnish patients

Patrakka, Jaakko; Kestilä, Marjo; Wartiovaara, Jorma; Ruotsalainen, Vesa; Tissari, Päivi; Lenkkeri, Ulla; Männikkö, Minna; Visapää, Ilona; Holmberg, Christer; Rapola, Juhani; Tryggvason, Karl; Jalanko, Hannu

doi:10.1046/j.1523-1755.2000.00254.x

Cited by 258 publications

(217 citation statements)

References 15 publications

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“…As exampled by congenital nephrotic syndrome of the Finnish type, genetic mutations of protein components within this microdomain lead to similar effects. 9 Podocin is another example for a protein that seems to be indispensable for the function of the slit diaphragm. Podocin is a recently identified protein of the raft-associated stomatin family 41 whose gene NPHS2 is mutated in families with autosomal-recessive steroidresistant nephrotic syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…6 -8 Together with the fact that congenital nephrotic syndrome of the Finnish type patients lacking functional nephrin fail to develop intact slit diaphragms, these findings have led to the conclusion that nephrin is a key component of the slit diaphragm. 9 The function of nephrin at the slit diaphragm is so far not very well understood. Based on its structure, nephrin has been proposed to oligomerize in a homophilic manner between neighboring foot processes.…”

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confidence: 99%

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Involvement of Lipid Rafts in Nephrin Phosphorylation and Organization of the Glomerular Slit Diaphragm

Simons

Schwarz

Kriz

et al. 2001

The American Journal of Pathology

145

126

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NPHS1 has recently been identified as the gene whose mutations cause congenital nephrotic syndrome of the Finnish type. The respective gene product nephrin is a transmembrane protein expressed in glomerular podocytes and primarily localized to the glomerular slit diaphragm. This interpodocyte junction functions in the glomerular filtration by restricting the passage of plasma proteins into the urinary space in a size-selective manner. The functional role of nephrin in this filtration process is so far not very well understood. In this study, we show that nephrin associates in an oligomerized form with signaling microdomains, also known as lipid rafts, and that these localize to the slit diaphragm. We also show that the nephrin-containing rafts can be immunoisolated with the 27A antibody recognizing a podocyte-specific 9-Oacetylated GD3 ganglioside. In a previous study it has been shown that the in vivo injection of this antibody leads to morphological changes of the filtration slits resembling foot process effacement. Here, we report that, in this model of foot process effacement, nephrin dislocates to the apical pole of the narrowed filtration slits and also that it is tyrosine phosphorylated. We suggest that lipid rafts are important in the spatial organization of the glomerular slit diaphragm under physiological and pathological conditions. One of the main functions of the kidney is formation of the primary urine in the glomerulus by plasma ultrafiltration. The structural correlate of ultrafiltration is the glomerular capillary wall with its distinctly layered filtration barrier. It consists of the fenestrated vascular endothelium, the glomerular basement membrane, and a layer of morphologically highly specialized epithelial cells, podocytes.Podocytes form a tight network of multiple interdigitating cellular extensions, called foot processes, which are bridged by so-called "slit diaphragms." 1 The filtration barrier is freely permeable for water, small solutes, and ions but does not allow passage for proteins larger than albumin and other large molecules. The charge selectivity in this process has been attributed to the glomerular basement membrane whereas the slit diaphragm supposedly plays a major role in the size selectivity. 2,3 The importance of the filtration barrier is reflected by a number of human diseases in which the filtration barrier function is disrupted resulting in the loss of plasma proteins into the urine. Patients with persistent proteinuria ultimately develop a nephrotic syndrome with a variety of symptoms including edema, hypoalbuminemia, and hyperlipidemia. 4

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Involvement of Lipid Rafts in Nephrin Phosphorylation and Organization of the Glomerular Slit Diaphragm

Simons

Schwarz

Kriz

et al. 2001

The American Journal of Pathology

145

126

View full text Add to dashboard Cite

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“…An acquired primary dysregulation of podocytes is described in collapsing idiopathic focal segmental glomerulosclerosis and in HIV-associated nephropathy (Barisoni et al 1999(Barisoni et al ,2000. A congenitally altered genotype and phenotype of podocytes is also known, such as in congenital nephrotic syndrome, an inherited autosomal recessive disease in which the gene mutated codes for nephrin, a cell surface protein of podocytes (Patrakka et al 2000). Because cells with elevated DTD levels are generally more sensitive to bioreductive antitumor agents such as MMC, a high expression of DTD explains, in theory, a selective toxicity towards podocytes of DTDbioactivated compounds.…”

Section: Discussionmentioning

confidence: 99%

NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

Zappa

Ward

Pedrinis

et al. 2003

J Histochem Cytochem.

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(FZ,TW,JB,AM), and Institute of Pathology of Southern Switzerland, Locarno, Switzerland (EP) S U M M A R Y NAD(P)H:quinone oxidoreductase 1 (NQO1; DT-diaphorase; DTD) is a cytosolic two-electron reductase, and compounds of the quinone family such as mitomycin C are efficiently bioactivated by this enzyme. The observation that DT-diaphorase is highly expressed in many cancerous tissues compared to normal tissues has provided us with a potentially selective target that can be exploited in the design of novel anticancer agents. Because of the relative lack of information about the cell-specific expression of DT-diaphorase, the purpose of this study was to map the distribution of this enzyme in normal human tissues. Fifteen tissue samples from normal human kidney were analyzed for expression of DT-diaphorase by immunohistochemistry (two-step indirect method). We found a specific high expression of DT-diaphorase in glomerular visceral epithelial cells (podocytes). These results suggest that a high expression of DT-diaphorase in podocytes could play a major role in the pathogenesis of renal toxicity and mitomycin C-induced hemolytic uremic syndrome, in which injury to the glomerular filtration mechanism is the primary damage, leading to a cascade of deleterious events including microangiopathic hemolytic anemia and thrombocytopenia. This observation has potential therapeutic implications because the DT-diaphorase metabolic pathway is influenced by many agents, including drugs, diet, and environmental cell factors such as pH and oxygen tension.

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“…Мутация гена NPHS1, кодирующего нефрин, ведет к отсутствию щелевой мембраны, что проявля-ется клинически тяжелым нефротическим синдро-мом финского типа начиная с антенатального пери-ода развития ребенка. Это показано при электронной микроскопии фрагментов клубочка у пациентов фин-ской национальности с врожденным нефротическим синдромом [16]. Особенностью гломерул при этом заболевании оказывается их атубулярный характер, что способствует гипертрофии оставшихся «нормаль-ных клубочков» и развитию микрокистоза [17].…”

Section: вторичный нефротический синдромunclassified

Nephrotic Syndrome: Past, Present and Future

Ignatova¹,

Длин²

2017

Ross. vestn. perinatol. pediatr.

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Congenital nephrotic syndrome (NPHS1): Features resulting from different mutations in Finnish patients

Abstract: The most common NPHS1 gene mutations, Fin-major and Fin-minor, both lead to an absence of nephrin and podocyte slit diaphragms, as well as a clinically severe form of NPHS1, the Finnish type of congenital nephrotic syndrome.

Cited by 258 publications

References 15 publications

Involvement of Lipid Rafts in Nephrin Phosphorylation and Organization of the Glomerular Slit Diaphragm

Involvement of Lipid Rafts in Nephrin Phosphorylation and Organization of the Glomerular Slit Diaphragm

NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

Nephrotic Syndrome: Past, Present and Future

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