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1.
Skálová S Podhola M Vondrák K Chernin G 《Acta medica (Hradec Králové) / Universitas Carolina, Facultas Medica Hradec Králové》2010,53(3):157-159
Podocin mutations (NPHS2 gene) are mostly responsible for steroid-resistant nephrotic syndrome (SRNS) of childhood onset. Patients with NPHS2 gene mutations do not respond to corticoids and other immunosuppressive agents; partial remission can be rarely induced by cyclosporin A. We present a boy, where SRNS was diagnosed within first year of life. By the age of 15 years, proteinuria reached 9000 mg/24 h, cholesterolemia 15 mmol/L, albuminemia 19.6 g/L, in spite of combined therapy with cyclosporine A, methylprednisolone, enalapril and losartan. At that time a combined heterozygous form of two NPHS2 gene mutations (p.R138Q and p.V290M) was diagnosed, methylprednisolone was discontinued and patient underwent ten plasmapheresis procedures. This resulted in clinical improvement (proteinuria 3000 mg/24 h, S-cholesterol 6 mmol/L, albumin 30g/L) lasting for three years. In conclusion, plasmapheresis can result in clinical improvement and stabilization of SRNS caused by podocine mutation, before renal replacement therapy is initiated. 相似文献
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Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits in between. These are bridged by the slit diaphragm, which plays a major role in establishing the selective permeability of the glomerular filtration barrier. We searched Medline and Pubmed using the combination of keywords "NPHS2", "podocin", "steroid-resistant nephrotic syndrome," and "genetics" to identify studies describing an association between NPHS2 gene and renal disease. The highly dynamic foot processes contain an actin-based contractile apparatus comparable to that of smooth muscle cells. Mutations affecting several podocyte proteins lead to rearrangement of the cytoskeleton, disruption of the filtration barrier, and subsequent renal disease. The fact that the dynamic regulation of the podocyte cytoskeleton is vital to kidney function has led to podocytes emerging as an excellent model system for studying actin cytoskeleton dynamics in a physiological context. Injury to podocytes leads to proteinuria, a hallmark of most glomerular diseases. Recent studies have led to a considerable increase in our understanding of podocyte biology including composition and arrangement of the cytoskeleton involved in the control of ultrafiltration. Moreover, disturbances of podocyte architecture resulting in the retraction of foot processes and proteinuria appear to be a common theme in the progression of an acquired glomerular disease. In hereditary nephrotic syndromes identified over the last few years, all mutated gene products were localized in podocytes. This review integrates our recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier. 相似文献
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Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration 总被引:15,自引:0,他引:15
Koziell A Grech V Hussain S Lee G Lenkkeri U Tryggvason K Scambler P 《Human molecular genetics》2002,11(4):379-388
Mutations of the novel renal glomerular genes NPHS1 and NPHS2 encoding nephrin and podocin cause two types of severe nephrotic syndrome presenting in early life, Finnish type congenital nephrotic syndrome (CNF) and a form of autosomal recessive familial focal segmental glomerulosclerosis (SRN1), respectively. To investigate the mechanisms by which mutations might cause glomerular protein leak, we analysed NPHS1/NPHS2 genotype/phenotype relationships in 41 non-Finnish CNF patients, four patients with congenital (onset 0 to 3 months) focal segmental glomerulosclerosis and five patients with possible SRN1 (onset 6 months to 2 years). We clarify the range of NPHS1 mutations in CNF, detecting mutation 'hot-spots' within the NPHS1 coding sequence. In addition, we describe a novel discordant CNF phenotype characterized by variable clinical severity, apparently influenced by gender. Moreover, we provide evidence that CNF may be genetically heterogeneous by detection of NPHS2 mutations in some CNF patients in whom NPHS1 mutations were not found. We confirm an overlap in the NPHS1/NPHS2 mutation spectrum with the characterization of a unique di-genic inheritance of NPHS1 and NPHS2 mutations, which results in a 'tri-allelic' hit and appears to modify the phenotype from CNF to one of congenital focal segmental glomerulosclerosis (FSGS). This may result from an epistatic gene interaction, and provides a rare example of multiple allelic hits being able to modify an autosomal recessive disease phenotype in humans. Our findings provide the first evidence for a functional inter-relationship between NPHS1 and NPHS2 in human nephrotic disease, thus underscoring their critical role in the regulation of glomerular filtration. 相似文献
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Congenital nephrotic syndrome, Finnish type (CNF or NPHS1), is an autosomal recessive disease characterized by massive proteinuria and development of nephrotic syndrome shortly after birth. The disease is most common in Finland, but many patients have been identified in other populations. The disease is caused by mutations in the gene for nephrin which is a key component of the glomerual ultrafilter, the podocyte slit diaphragm. A total of 30 mutations have been reported in the nephrin gene in patients with congenital nephrotic syndrome worldwide. In the Finnish population, two main mutations have been found. These two nonsense mutations account for over 94% of all mutations in Finland. Most mutations found in non-Finnish patients are missense mutations, but they include also nonsense and splice site mutations, as well as deletions and insertions. This mutation update summarizes the nature of all previously reported nephrin mutations and, additionally, describes 20 novel mutations recently identified in our laboratory. 相似文献
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Nora Franceschini Kari E North Jeffrey B Kopp Louise McKenzie Cheryl Winkler 《Genetics in medicine》2006,8(2):63-75
Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted. 相似文献
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Joven J Arcelús R Camps J Ordóñez-Llanos J Vilella E González-Sastre F Blanco-Vaca F 《Journal of molecular medicine (Berlin, Germany)》2000,78(3):147-154
Hyperhomocyst(e)inemia is an independent risk factor for atherothrombosis in several clinical settings in which renal function is impaired, but its prevalence in the nephrotic syndrome has not been investigated in detail, even though this syndrome provides an excellent model in which to study a possible link between albuminuria, proteinuria, and hyperhomocyst(e)inemia. We obtained plasma and urine from 27 patients with biopsy-confirmed membranous glomerulonephritis presenting nephrotic syndrome and 27 matched controls and determined the concentrations of homocyst(e)ine and proteins considered putative markers of glomerular and tubular function. Hyperhomocyst(e)inemia, defined as the mean +SD of the plasma homocyst(e)ine concentration of the controls [plasma homocyst(e)ine concentration >10.8 micromol/l] was present in 26% of the patients with nephrotic syndrome but in only 7.4% of the controls. Furthermore, the degree of hyperhomocyst(e)inemia was more severe in the nephrotic patients than in the controls. The existence of renal failure, tubular damage, and, interestingly, relatively well conserved glomerular function barrier were the main predictors of increased levels of plasma homocyst(e)ine. In conclusion, hyperhomocyst(e)inemia is a frequent cardiovascular risk factor present in patients with nephrotic syndrome and renal failure, but it is not directly associated with proteinuria. 相似文献
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Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. Recently, DC-SIGN has been shown to be the major M. tuberculosis receptor on dendritic cells (DCs). The aim of this study was to investigate the influence of DC-SIGN functional polymorphisms -336G/A SNP in the promoter region and insertion/deletion in the "neck" region on the predisposition to tuberculosis. We performed an association study in 110 HIV-negative tuberculosis patients and 299 matched controls. In addition, a total of 155 healthy controls were screened for the tuberculin skin test (TST). DC-SIGN -336 SNP detection was performed by the real-time polymerase chain reaction technology, using the TaqMan 5' allele. The insertion/deletion in the "neck" region was analyzed by polymerase chain reaction with specific primers. Although an increased frequency of the G allele in tuberculosis patients (23%), as compared with controls (19%), was observed, differences were not statistically significant (OR = 1.31, 95% CI = 0.89-1.94, P = 0.14). On the other hand, DC-SIGN repeat polymorphism in the "neck" region had a very low frequency in the analyzed population. We conclude that the studied polymorphisms are not relevant risk factors for developing tuberculosis in Northwestern Colombian individuals. 相似文献
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The occurrence of nephrotic syndrome was studied in different types of glomerulonephritis. In 284 consecutive adult cases the diagnosis was confirmed by the histological evaluation of percutaneous renal biopsy. Nephrotic syndrome was more frequent in minimal change glomerulonephritis, in focal sclerosis and in membranous nephropathy. The incidence of glomerulonephritis decreases, while the relative incidence of nephrotic syndrome increases with age. Glomerulonephritis is more frequent in men whereas the relative incidence of nephrotic syndrome is higher in women. 相似文献
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F. C. Reubi A. Seiler K. Farina 《Journal of molecular medicine (Berlin, Germany)》1984,62(13):621-630
Summary Transient or persistent renal glycosuria may occur in patients with the nephrotic syndrome. In an attempt to elucidate its mechanism, glucose titration experiments were performed in 20 nephrotic patients. The type A titration curve was found in one and type B in four patients with severe organic changes and low glomerular filtration rate. The remaining subjects displayed a particular type of curve (type C) characterized by a low point of splay but an otherwise almost physiological tracing. In type B and C patients the maximal rate of reabsorption per ml glomerular filtrate (TmG/GFR) was significantly increased and correlated inversely with the filtration fraction. In these patients the point of splay correlated with the glomerular filtration rate and the sodium clearance, but not with the plasma albumin concentration or the rate of proteinuria. These observations suggest that type A was due to diffuse tubular atrophy, and type B to increased nephron heterogeneity resulting from chronic organic changes. Type C was presumably caused by a potentially reversible alteration of the late proximal or distal glucose transport related to the nephrotic syndrome itself. 相似文献
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The case was a one year and four months old boy, who had been diagnosed as congenital nephrotic syndrome on the 4th day of life. He died of septicemia from peritonitis. Large pale kidneys, dilated trunk of pulmonary artery, and thickened left atrial endocardium were observed at autopsy. Renal histology seemed to be compatible with congenital nephrotic syndrome of the Finnish type. Viral antigens of herpes simplex type 1 and varicella-zoster in paraffin-embedded sections were proven to be negative. Besides renal change, increased number of pancreatic islets without hypertrophy was noticed. 相似文献
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Cell coat of podocytes in patients with nephrotic syndrome 总被引:1,自引:0,他引:1
Renal biopsies from 23 patients with the nephrotic syndrome and five patients with slight or no proteinuria were examined for the presence of cell coat of podocytes by light and electron microscopy. Of those with nephrotic syndrome, five had minimal change disease, nine focal glomerular sclerosis, six membraneous nephropathy and three amyloidosis. Colloidal iron and phosphotungstic acid stains were used for the demonstration of anionic and neutral polysaccharide components of the cell coat. On light microscopy, the colloidal iron reaction showed a reduction in intensity of the stain in glomeruli of patients with massive proteinuria, as compared to those with slight or no proteinuria. On electron microscopy, only the cell coat lining the surface of the foot processes disappeared parallel to the loss of these structures, while the coat covering the surface facing the urinary space remained unchanged with both stains. 相似文献
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Alena antav Jiina Zapletalov Kamila Michlkov Stanislava Hankov Frantiek Kopiva Jií antavý Jaroslav Duek Duana Kleinov 《American journal of medical genetics. Part A》1994,49(3):270-273
The first symptoms of immunoosseous dysplasia were growth retardation and myopia. Nephrotic syndrome was diagnosed at the age of 8 years. Skeletal roentgenograms showed spondyloepiphyseal dysplasia. In the renal biopsy there was nodular accumulations of PAS-positive hyaline material at the base of the granular stalks. There was lymphopenia with decreased CD4 and CD8 subpopulations. The condition of the patient gradually worsened until she died unexpectedly at 10 years with clincal symptoms of encephalitis. Autopsy documented cytomegaloviral pneumonia and advanced mesangioproliferative glomerulonephritis. In the spleen there was PAS-positive hyaline material massively infiltrating the walls of the central arterioles of the splenic follicles. There was marked depletion of lymphocytes in the spleen and in lymphnodes. The differential diagnosis of immunoosseous dysplasia in the framework of spondyloepiphyseal dysplasia is discussed. © 1994 Wiley-Liss, Inc. 相似文献
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Helge Martens Imke Hennies Maike Getwan Anne Christians Anna-Carina Weiss Frank Brand Ann Christin Gjerstad Arne Christians Zoran Gucev Robert Geffers Tom Seeman Andreas Kispert Velibor Tasic Anna Bjerre Soeren S. Lienkamp Dieter Haffner Ruthild G. Weber 《European journal of human genetics : EJHG》2020,28(12):1681
Although over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.Subject terms: Genetics research, Mutation, Development, Medical genetics 相似文献
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Nansi S. Boghossian Robert J. Sicko Andreas Giannakou Aggeliki Dimopoulos Michele Caggana Michael Y. Tsai Edwina H. Yeung Nathan Pankratz Benjamin R. Cole Paul A. Romitti Marilyn L. Browne Ruzong Fan Aiyi Liu Denise M. Kay James L. Mills 《European journal of medical genetics》2018,61(3):145-151
Prune belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a rare congenital disorder characterized by absence or hypoplasia of the abdominal wall musculature, urinary tract anomalies, and cryptorchidism in males. The etiology of PBS is largely unresolved, but genetic factors are implicated given its recurrence in families. We examined cases of PBS to identify novel pathogenic copy number variants (CNVs). A total of 34 cases (30 males and 4 females) with PBS identified from all live births in New York State (1998–2005) were genotyped using Illumina HumanOmni2.5 microarrays. CNVs were prioritized if they were absent from in-house controls, encompassed ≥10 consecutive probes, were ≥20 Kb in size, had ≤20% overlap with common variants in population reference controls, and had ≤20% overlap with any variant previously detected in other birth defect phenotypes screened in our laboratory. We identified 17 candidate autosomal CNVs; 10 cases each had one CNV and four cases each had two CNVs. The CNVs included a 158 Kb duplication at 4q22 that overlaps the BMPR1B gene; duplications of different sizes carried by two cases in the intron of STIM1 gene; a 67 Kb duplication 202 Kb downstream of the NOG gene, and a 1.34 Mb deletion including the MYOCD gene. The identified rare CNVs spanned genes involved in mesodermal, muscle, and urinary tract development and differentiation, which might help in elucidating the genetic contribution to PBS. We did not have parental DNA and cannot identify whether these CNVs were de novo or inherited. Further research on these CNVs, particularly BMP signaling is warranted to elucidate the pathogenesis of PBS. 相似文献