Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idiopathic nephrotic syndrome (INS) in childhood is characterized by massive proteinuria and minimal glomerular changes. Most patients with INS respond to steroid therapy. INS is generally regarded as a sporadic disease with favorable outcome. We investigated a distinct subgroup of nephrosis--the familial form of steroid resistant INS (SRN). These patients always progress to end-stage renal failure within a few years and show absence of recurrence of the disease after renal transplantation. The occurrence of the disorder in siblings and the high incidence of inbreeding in these families made an autosomal recessive mode of inheritance very likely. We performed whole genome linkage analysis in nine multiplex families of European or Northern African origin. Our results allowed us to assign a disease locus (SRN1) to a defined chromosomal region on 1q25-1q31, thus confirming the existence of a distinct entity of autosomal recessive nephrosis. Exclusion of linkage to the entire region in one family proves genetic heterogeneity.
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PMID:Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. 858 95

Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrotic syndrome, which is characterized by early childhood onset of proteinuria, rapid progression to end-stage renal disease and focal segmental glomerulosclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25-31 and we report here its identification by positional cloning. NPHS2 is almost exclusively expressed in the podocytes of fetal and mature kidney glomeruli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprising nonsense, frameshift and missense mutations, to segregate with the disease, demonstrating a crucial role for podocin in the function of the glomerular filtration barrier.
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PMID:NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. 1074 96

Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte proteins nephrin and podocin, cause steroid-resistant proteinuria. In addition, mice lacking CD2-associated protein (CD2AP) develop a nephrotic syndrome that resembles NPHS mutations suggesting that all three proteins are essential for the integrity of glomerular podocytes. Although the precise glomerular function of either protein remains unknown, it has been suggested that nephrin forms zipper-like interactions to maintain the structure of podocyte foot processes. We demonstrate now that nephrin is a signaling molecule, which stimulates mitogen-activated protein kinases. Nephrin-induced signaling is greatly enhanced by podocin, which binds to the cytoplasmic tail of nephrin. Mutational analysis suggests that abnormal or inefficient signaling through the nephrin-podocin complex contributes to the development of podocyte dysfunction and proteinuria.
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PMID:Interaction with podocin facilitates nephrin signaling. 1156 57

Podocin mutations (NPHS2 gene) are responsible for the autosomal recessive form of steroid-resistant nephrotic syndrome. As a result of a screening for these gene alterations in a cohort of Italian patients with nonfamilial nephrotic syndrome and histologic focal segmental glomerulosclerosis (FSGS), nine patients with NPHS2 gene homozygous or composite heterozygous mutations were found. In addition to the previously described defects, two novel mutations at exon 4 were identified (frameshift, L169P); four single nucleotide polymorphisms (SNPs) and one dinucleotide repeat were also identified. On the basis of haplotype analysis, a founder effect was suggested for the 419delG mutation, the most frequently observed in the patients studied. Patients carrying NPHS2 mutations and without a family history of nephrotic syndrome were indistinguishable from those with idiopathic FSGS on the basis of the clinical phenotype. Two of the nine patients had normal renal function at 3 and 10 yr of age, despite the presence of the nephrotic syndrome. The other seven had reached end-stage renal failure at a mean age of 9.6 yr (range, 4 to 17 yr) and had received renal allografts. In those presenting with end-stage renal failure, the clinical and laboratory features both before and after transplantation were similar, including the age at onset, the amount of proteinuria, and the absence of any response to steroids and other immunosuppressants. Finally, two children presented recurrence of mild proteinuria after transplantation, which promptly remitted after plasmapheresis combined with cyclophosphamide. These data demonstrate that podocin mutations in nonfamilial cases of steroid-resistant nephrotic syndrome are frequent and may be due in one case to a founder effect. The pretransplantation and posttransplantation outcomes in the group of patients with mutations of the podocin gene are similar to classical idiopathic FSGS, including the possibility of recurrence of proteinuria that is mild and responsive to plasmapheresis. These observations support a role of molecular screening of the podocin gene in patients with nephrotic syndrome before immunosuppressive treatment is started.
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PMID:Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. 1172 43

Autosomal recessive steroid-resistant nephrotic syndrome (SRINS) belongs to the heterogeneous group of familial nephrotic syndrome and represents a frequent cause of end-stage renal disease in childhood. This kidney disorder is characterized by early onset of proteinuria, progression to end-stage renal disease, and histologic findings of focal segmental glomerulosclerosis, minimal change nephrotic syndrome, or both. A causative gene, NPHS2, has been mapped to chromosome 1q25-q31 and was recently identified by positional cloning. This study reports five novel NPHS2 mutations: A284V, R196P, V290M, IVS4-1G-->T, and 460-467insT in 12 (46%) of 26 multiplex families and in 7 (28%) of 25 single patients with the clinical diagnosis of a SRINS. Because NPHS2 mutations were found in nearly 30% of these patients with "sporadic" SRINS, mutational analysis should also be performed in these patients. Besides better classification of the disease entity, identification of NPHS2 mutations may save some of these patients from unnecessary steroid treatment and also permit the prediction of absence of disease recurrence after kidney transplantation.
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PMID:Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. 1180 90

A plasma factor displaying permeability activity in vitro and possibly determining proteinuria has been hypothesized in idiopathic focal segmental glomerulosclerosis (FSGS). In vitro permeability activity (P(alb)) was determined in sera of five patients with autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), an inherited condition indistinguishable from idiopathic FSGS on clinical grounds, but in which proteinuria is determined by homozygous mutations of podocin, a key component of the glomerular podocyte. All patients had presented intractable proteinuria with nephrotic syndrome; four developed renal failure and received a renal allograft. For comparison, sera from 31 children with nephrotic syndrome were tested. Pretransplant P(alb) was high in all cases (mean 0.81 +/- 0.06), equivalent to levels observed in idiopathic FSGS. Overall, P(alb) did not correlate with proteinuria. The posttransplant outcome was complicated in two patients by recurrence of proteinuria after 10 and 300 d, respectively, that responded to plasmapheresis plus cyclophosphamide. P(alb) levels were high at the time of the recurrence episodes and steadily decreased after plasmapheresis, to reach normal levels in the absence of proteinuria after the seventh cycle. In an attempt to explain high P(alb) in these patients, putative inhibitors of the permeability activity were studied. Coincubation of serum with homologous nephrotic urine reduced P(alb) to 0, whereas normal urine did not determine any change, which suggests loss of inhibitory substances in nephrotic urine. The urinary levels of the serum P(alb) inhibitors apo J and apo E were negligible in all cases, thus suggesting that other urinary inhibitors were responsible for the neutralizing effect. These data indicate that P(alb) is high in NPHS2, probably resulting from loss of inhibitors in urine. Lack of correlation of P(alb) with proteinuria suggests a selective loss of inhibitors. As in idiopathic FSGS, proteinuria may also recur after renal transplantation in NPHS2 patients, and post-transplant proteinuria is associated with high P(alb). The relationship between elevated P(alb) and proteinuria in NPHS2 remains to be determined.
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PMID:Serum glomerular permeability activity in patients with podocin mutations (NPHS2) and steroid-resistant nephrotic syndrome. 1208 92

Molecular components of the glomerular filtration mechanism play critical roles in renal diseases. Many of these components are produced during the final stages of differentiation of glomerular visceral epithelial cells, also known as podocytes. While basic domain leucine zipper (bZip) transcription factors of the Maf subfamily have been implicated in cellular differentiation processes, Kreisler (Krml1/MafB), the gene affected in the mouse kreisler (kr) mutation, is known for its role in hindbrain patterning. Here we show that mice homozygous for the kr(enu) mutation develop renal disease and that Kreisler is essential for cellular differentiation of podocytes. Consistent with abnormal podocyte differentiation, kr(enu) homozygotes show proteinuria, and fusion and effacement of podocyte foot processes, which are also observed in the nephrotic syndrome. Kreisler acts during the final stages of glomerular development-the transition between the capillary loop and mature stages-and downstream of the Pod1 basic domain helix-loop-helix transcription factor. The levels of Podocin, the gene mutated in autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), and Nephrin, the gene mutated in congenital nephrotic syndrome of the Finnish type (NPHS1), are slightly reduced in kr(enu)/kr(enu) podocytes. However, these observations alone are unlikely to account for the aberrant podocyte foot process formation. Thus, Kreisler must regulate other unknown genes required for podocyte function and with possible roles in kidney disease.
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PMID:The mouse Kreisler (Krml1/MafB) segmentation gene is required for differentiation of glomerular visceral epithelial cells. 1221 15

Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte proteins nephrin and podocin, cause steroid-resistant proteinuria. In addition, mice lacking NEPH1 develop a nephrotic syndrome that resembles NPHS mutations, suggesting that all three proteins are essential for the integrity of glomerular podocytes. Podocin interacts with the C-terminal domain of nephrin and facilitates nephrin-dependent signaling. NEPH1, a member of the immunoglobulin superfamily, is structurally related to nephrin. We report now that NEPH1 belongs to a family of three closely related proteins that interact with the C-terminal domain of podocin. All three NEPH proteins share a conserved podocin-binding motif; mutation of a centrally located tyrosine residue dramatically lowers the affinity of NEPH1 for podocin. NEPH1 triggers AP-1 activation similarly to nephrin but requires the presence of Tec family kinases for efficient transactivation. We conclude that NEPH1 defines a new family of podocin-binding molecules that are potential candidates for hereditary nephrotic syndromes not linked to either NPHS1 or NPHS2.
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PMID:NEPH1 defines a novel family of podocin interacting proteins. 1242 24

Podocin is an integral membrane protein encoded by NPHS2, which is mapped to 1q25-31 and is exclusively expressed in glomerular podocytes. NPHS2 mutations are responsible for autosomal recessive familial steroid-resistant nephrotic syndrome (SRNS) with minor glomerular abnormalities or focal segmental glomerulosclerosis (FSGS), which is characterized by early childhood onset (age less than 6 years) and rapid progression to chronic renal insufficiency. This gene mutation is also responsible for an adolescent/adult onset form of autosomal recessive familial FSGS with heavy proteinuria. It has been demonstrated that sporadic SRNS and heavy proteinuria are also due to NPHS2 gene mutations. We isolated genomic DNA from 36 Japanese children with chronic renal insufficiency caused by SRNS or heavy proteinuria, and analyzed all eight exons and exon-intron boundaries of NPHS2 using the polymerase chain reaction and direct sequencing. The age at onset of disease was 3.9+/-0.5 years. There were 29 patients with SRNS and 7 with heavy proteinuria without nephrotic syndrome at the onset, but all patients developed chronic renal insufficiency 4.6+/-0.8 years after the onset. A new homozygous missense variant of NPHS2, G34E (G101A) in exon 1, was detected in 1 of 36 patients. However, this homozygous variant was also found in 1 of 44 normal controls, suggesting that the mutation is a polymorphism. Two silent variants (T954C and A1038G) in exon 8 of this gene were also identified in some of the patients and normal controls, indicating that the silent variants are also polymorphisms. There was no significant difference in the genotypic and allelic frequencies of T954C and A1038G polymorphisms between the patients and normal controls. In conclusion, NPHS2 gene mutations are not a major cause of chronic renal insufficiency caused by sporadic SRNS or heavy proteinuria in Japanese children.
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PMID:NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children. 1268 58

Mutations of NPHS1 or NPHS2, the genes encoding nephrin and podocin, as well as the targeted disruption of CD2-associated protein (CD2AP), lead to heavy proteinuria, suggesting that all three proteins are essential for the integrity of glomerular podocytes, the visceral glomerular epithelial cells of the kidney. It has been speculated that these proteins participate in common signaling pathways; however, it has remained unclear which signaling proteins are actually recruited by the slit diaphragm protein complex in vivo. We demonstrate that both nephrin and CD2AP interact with the p85 regulatory subunit of phosphoinositide 3-OH kinase (PI3K) in vivo, recruit PI3K to the plasma membrane, and, together with podocin, stimulate PI3K-dependent AKT signaling in podocytes. Using two-dimensional gel analysis in combination with a phosphoserine-specific antiserum, we demonstrate that the nephrin-induced AKT mediates phosphorylation of several target proteins in podocytes. One such target is Bad; its phosphorylation and inactivation by 14-3-3 protects podocytes against detachment-induced cell death, suggesting that the nephrin-CD2AP-mediated AKT activity can regulate complex biological programs. Our findings reveal a novel role for the slit diaphragm proteins nephrin, CD2AP, and podocin and demonstrate that these three proteins, in addition to their structural functions, initiate PI3K/AKT-dependent signal transduction in glomerular podocytes.
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PMID:Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. 1283 77


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