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A gene locus for nephronophthisis type 1 (NPH1) has been mapped by linkage analysis to chromosome 2q13.

We performed a haplotype analysis in 16 NPH families with at least two affected patients with the typical history, clinical signs and histology of NPH using microsatellite markers of the NPH1 genetic region.

By demonstration of a recombinant event marker D2S1893 was identified as a novel centromeric flanking marker to the NPH1 critical genetic region.

Absence of linkage to the NPH1 locus in six NPH families confirmed the existence of at least one additional gene locus for NPH.

Linkage to the NPH1 locus was demonstrated in 10 families.

These data permit for the first time the study of the development of renal failure in a subset of NPH1 families, which is most likely homogeneous with regard to the responsible gene locus.

We present a statistical description of serial serum creatinine measurements in NPH1.

In summary, the new marker provides a diagnostic tool to aid in the diagnosis of NPH, while the progression charts offer a standard for an assessment of the rate of progression to ESRD for patients with NPH1 to be used in future therapeutic trials and for a prediction of the individual course of the disease.

nephrocystin

Nephrocystin and ciliary defects not only in the kidney?

nephrocystin

We highlight our present knowledge on nephrocystin as the defective protein in nephronophthisis type I.

nephrocystin

Nephrocystin has been localized to the ciliary transition zone not only of renal tubule cells but also of respiratory and retinal cilia.

Juvenile or type 1 nephronophthisis (NPH1), an autosomal recessive cystic kidney disease, represents the most common genetic cause of end-stage renal disease in the first two decades of life.

Because the disease is caused by large homozygous deletions of the NPHP1 gene in approximately 66% of patients with nephronophthisis, molecular genetic testing offers a method for the definite diagnosis of NPH1 and avoids the invasive procedure of renal biopsy.

Because the disease is caused by large homozygous deletions of the NPHP1 gene in approximately 66% of patients with nephronophthisis, molecular genetic testing offers a method for the definite diagnosis of NPH1 and avoids the invasive procedure of renal biopsy.

We recently developed an algorithm for molecular genetic diagnosis of NPH1 that efficiently detects homozygous deletions.

However, a major limitation remained for the detection of heterozygous deletions that cause NPH1 in combination with point mutations at the other NPHP1 allele.

However, a major limitation remained for the detection of heterozygous deletions that cause NPH1 in combination with point mutations at the other NPHP1 allele.

Because a partial sequence from the NPHP1 region recently became available through the Human Genome Projects, we exploited this information to develop novel polymorphic markers from this genetic region for the detection of heterozygous deletions of NPHP1, thus bridging the diagnostic gap.

Because a partial sequence from the NPHP1 region recently became available through the Human Genome Projects, we exploited this information to develop novel polymorphic markers from this genetic region for the detection of heterozygous deletions of NPHP1, thus bridging the diagnostic gap.

Five novel polymorphic microsatellites positioned within the large common NPHP1 deletion were generated.

Two multiplex polymerase chain reaction sets using two and three polymorphic markers from the NPHP1 deletion region together with one positive control marker allowed four different diagnostic problems to be solved in one diagnostic setup: (1) detection of the classic homozygous deletion of NPH1, (2) detection of a rare smaller homozygous deletion of NPH1, (3) testing for a heterozygous deletion, and (4) potential exclusion of linkage to NPHP1.

Two multiplex polymerase chain reaction sets using two and three polymorphic markers from the NPHP1 deletion region together with one positive control marker allowed four different diagnostic problems to be solved in one diagnostic setup: (1) detection of the classic homozygous deletion of NPH1, (2) detection of a rare smaller homozygous deletion of NPH1, (3) testing for a heterozygous deletion, and (4) potential exclusion of linkage to NPHP1.

Two multiplex polymerase chain reaction sets using two and three polymorphic markers from the NPHP1 deletion region together with one positive control marker allowed four different diagnostic problems to be solved in one diagnostic setup: (1) detection of the classic homozygous deletion of NPH1, (2) detection of a rare smaller homozygous deletion of NPH1, (3) testing for a heterozygous deletion, and (4) potential exclusion of linkage to NPHP1.

Two multiplex polymerase chain reaction sets using two and three polymorphic markers from the NPHP1 deletion region together with one positive control marker allowed four different diagnostic problems to be solved in one diagnostic setup: (1) detection of the classic homozygous deletion of NPH1, (2) detection of a rare smaller homozygous deletion of NPH1, (3) testing for a heterozygous deletion, and (4) potential exclusion of linkage to NPHP1.

JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle.

Fluorescence in situ hybridization for the diagnosis of NPHP1 deletion-related nephronophthisis on renal biopsy.

Approximately 60% of patients with a known genetic etiology of nephronophthisis are due to homozygous deletion of the NPHP1 gene.

We identified a total of 45 renal biopsies from young patients with chronic kidney disease of undetermined etiology and analyzed them for the possibility of nephronophthisis due to NPHP1 deletion using interphase fluorescence in situ hybridization and/or polymerase chain reaction.

Homozygous NPHP1 deletion was identified in 9 patients (20%).

Blinded histopathologic analysis was then performed and identified 6 lesions that were significantly more common in biopsies from patients with NPHP1 deletion-proven nephronophthisis than chronic kidney injury of other known etiologies.

There were, however, morphologic lesions that were strongly associated with NPHP1 deletion including tubular abnormalities such as diverticulum, florets, and macula densa-like change as well as interstitial Tamm-Horsfall aggregates, periglomerular fibrosis, and the absence of arteriosclerosis.

Awareness of the histopathologic pattern of injury in nephronophthisis combined with testing for NPHP1 deletion enables renal pathologists to provide a definitive pathologic and genetic diagnosis in a subset of patients with this disease.

Construction of a gene map of the nephronophthisis type 1 (NPHP1) region on human chromosome 2q12-q13.

Seven EST clones were localized to the NPHP1 region between D2S1893 and D2S1888.

Through FISH analysis the NPHP1 deletion region was localized to 2q12-q13.

In summary, our study provides a high-resolution physical map of the NPHP1 region with 7 precisely localized expressed sequences, 2 of which have recently been shown to be part of a gene for NPH.

Physical mapping of the gene for juvenile nephronophthisis (NPH1) by construction of a complete YAC contig of 7 Mb on chromosome 2q13.

A gene locus for nephronophthisis (NPH1) has been mapped by linkage analysis to chromosome 2q13.

We report here the construction of a complete YAC contig in the minimum genetic region for NPH1 by STS content mapping using clones of the CEPH YAC libraries.

Since D2S340 and D2S121 have previously been identified as flanking markers to the NPH1 gene, the new contig defines on a physical map the NPH1 minimum genetic region to a 6.4-Mb interval.

Since D2S340 and D2S121 have previously been identified as flanking markers to the NPH1 gene, the new contig defines on a physical map the NPH1 minimum genetic region to a 6.4-Mb interval.

As a novel assignment, expressed genes, some of which may be candidates for the disease, were localized to the NPH1 region.

This contig assembly provides the basis for closer definition of the NPH1 critical region through identification of more narrow flanking markers and for the construction of a transcriptional map of the region towards isolation of the NPH1 gene.

This contig assembly provides the basis for closer definition of the NPH1 critical region through identification of more narrow flanking markers and for the construction of a transcriptional map of the region towards isolation of the NPH1 gene.

NPHP1 mutations cause familial juvenile nephronophthisis type 1 (NPHP1, OMIM 256100), another autosomal recessive renal disease that usually occurs years after birth.

NPHP1 mutations cause familial juvenile nephronophthisis type 1 (NPHP1, OMIM 256100), another autosomal recessive renal disease that usually occurs years after birth.

We report an extremely rare case of concurrent mutations of LAMB2 and NPHP1 in a Chinese girl with isolated CNS and the association of the phenotype with novel non-truncating mutations of LAMB2.

In addition, compound heterozygous mutations of NPHP1 were identified in this child using next generation sequencing, and confirmed by Sanger sequencing.

CONCLUSION: Mutations of the LAMB2 and NPHP1 are present in infants with isolated CNS.

nephrocystin

Immunohistochemical examination using an antihuman TIN-ag monoclonal antibody showed attenuation or lack of TIN-ag staining along the renal tubular basement membrane, whereas nephrocystin staining was normal in renal tubules.

The reverse transcriptase-polymerase chain reaction analysis demonstrated mRNA expression of AGAT, BHMT, and Nph3 was significantly decreased in 12 RCC tissues.

CONCLUSION: Absence of AGAT, BHMT, and Nph3 is common events in clear cell RCC; hence, it may be involved in the development of RCC; therefore, they have the potential to be tumor markers for diagnosis, treatment, and prognosis of RCC patients.

High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients.

AIM: The present study was designed to explore mutations of NPHP2 and NPHP3 and clinical features in 18 Chinese infantile nephronophthisis (NPHP) patients.

AIM: The present study was designed to explore mutations of NPHP2 and NPHP3 and clinical features in 18 Chinese infantile nephronophthisis (NPHP) patients.

METHODS: Patients were subjected to screen for mutations in both NPHP2 and NPHP3, and clinical data were collected.

METHODS: Patients were subjected to screen for mutations in both NPHP2 and NPHP3, and clinical data were collected.

Eight of 17 (47.1%) patients detected were identified to have mutations in NPHP3, but none had a mutation in NPHP2.

Of the patients with NPHP3 mutations, four had compound heterozygous mutations, and the other four harboured single heterozygous mutations.

Ten of the NPHP3 mutations were novel.

Liver involvement was observed in all patients with NPHP3 mutations and congenital heart disease in two patients harbouring NPHP3 mutation of c.2369 T > C (p.L790P).

Liver involvement was observed in all patients with NPHP3 mutations and congenital heart disease in two patients harbouring NPHP3 mutation of c.2369 T > C (p.L790P).

CONCLUSIONS: In this group of infantile NPHP patients, mutations of NPHP3 were prevalent, whereas mutation of NPHP2 was absent.

Genotype to phenotype correlations were observed in patients with NPHP3 mutations and all patients with NPHP3 mutations showed renal-hepatic phenotype.

Genotype to phenotype correlations were observed in patients with NPHP3 mutations and all patients with NPHP3 mutations showed renal-hepatic phenotype.

We thus identified a new locus, NPHP4, for nephronophthisis.

Markers D1S2660 and D1S2642 are flanking NPHP4 at a 2.9-cM critical interval.

In one family with NPHP4, extensive genealogical studies were conducted, revealing consanguinity during the 17th century.

In addition, we were able to localize to the NPHP4 locus a new locus for Senior-Loken syndrome, an NPHP variant associated with retinitis pigmentosa.

Hildebrandt's group has shown that 85% of the SRNS cases with onset by 3 months of age and 66% with onset by 1 year of age can be explained by recessive mutations in one of four genes only (NPHS1, NPHS2, LAMB2, or WT1).

WT+STZ mice showed increased kidney:body weight ratio due to cell hypertrophy, increased albuminuria, decreased kidney nephrin, podocin, and podocyte number and increased transforming growth factor-beta and laminin compared with WT mice.

Nephrin, podocin, and podocyte number and effacement were restored, and transforming growth factor-beta and laminin levels were decreased in TLR2-/-+ STZ mice kidneys versus WT+STZ.

NOD2 knockout diabetic mice were protected from the hyperglycemia-induced reduction in nephrin expression.

Further, knockdown of NOD2 expression attenuated high glucose-induced nephrin downregulation in vitro, supporting an essential role of NOD2 in mediating hyperglycemia-induced podocyte dysfunction.

Similarly, HA abated the elevated levels of renal extracellular matrix/profibrotic proteins like collagen and fibronectin that deplete nephrin, a fundamental transmembrane protein that forms the scaffoldings of the podocyte slit diaphragm permitting small ions to filter, but not massive excretion of proteins, hence proteinuria.

Correspondingly, HA enhanced the aberrant expression of nephrin alongside other important regulators of podocyte like podocalyxin, podocin, and CD2AP, and improved renal function by reducing albuminuria/proteinuria, while increasing creatinine clearance.

CONCLUSIONS: HA improves renal function by attenuating histopathological lesions, suppressing inflammatory/oxidative mediators, abating profibrotic/extracellular matrix proteins, and reducing albuminuria/proteinuria, while concomitantly potentiating the HO-adiponectin-ANP axis, enhancing nephrin, podocin, podocalyxin, CD2AP and increasing creatinine clearance.

Decreased expression of nephrin and podocin and increased desmin-positive area in failing rats were restored by tolvaptan.

Glomerular stainings of nephrin and F-actin were focally impaired in the Ve group but were restored in the CH group.

Western blotting showed that the CH group had significantly increased renal nephrin expression compared with the Ve group.

Histopathological changes and immunohistochemical expressions of p53, EGFR, nephrin and AQP2 in the ACR-induced liver and kidney tissues were decreased after administration of morin.

In all lines, the quantities of NEPH1 and podocin proteins and NEPH1 and SYNPO mRNAs were comparable to glomeruli, while synaptopodin and nephrin proteins and NPHS1 and NPHS2 mRNAs were <5% of glomerular levels.

In all lines, the quantities of NEPH1 and podocin proteins and NEPH1 and SYNPO mRNAs were comparable to glomeruli, while synaptopodin and nephrin proteins and NPHS1 and NPHS2 mRNAs were <5% of glomerular levels.

Urinary exosomal protein leak in urine, examining podocyte health (podocalyxin, Wilm's tumor and nephrin) showed reduction with CG CONCLUSION: Low dose Canagliflozin has a beneficial effect on CD34+ cell function, serum biochemistry and urinary podocyte specific exosomes in type 2 diabetes.

Urinary Matrix Metalloproteinase-9 and Nephrin in Idiopathic Membranous Nephropathy: A Cross-Sectional Study.

Increased urinary excretion of matrix metalloproteinase-9 (MMP-9) and nephrin has been reported in a number of IMN-like glomerular diseases in which they reflected disease severity.

Methods: We quantified urinary MMP-9 and nephrin in 107 biopsy-proven IMN patients and 70 healthy subjects by enzyme-linked immunosorbent assay (ELISA).

Results: Urinary MMP-9 and nephrin were significantly higher in IMN compared to healthy controls.

Unlike nephrin, MMP-9 correlated significantly with proteinuria and was significantly higher among patients with nephrotic range proteinuria.

Conclusion: Our findings suggest that urinary MMP-9 holds a greater potential than urinary nephrin in monitoring the severity of IMN.

Protein levels of nephrin, podocin, CD2-associated protein, and podocalyxin were investigated using quantitative immunohistochemical assays.

Real-time PCR was used to determine the mRNA levels of nephrin, podocin, and podoplanin in microdissected glomeruli.

In most acquired renal diseases, except in IgA nephropathy, a marked reduction was observed at the protein levels of nephrin, podocin, and podocalyxin, whereas an increase of the glomerular mRNA levels of nephrin, podocin, and podoplanin was found, compared with controls.

The mean width of the podocyte foot processes was inversely correlated with the protein levels of nephrin (r = -0.443, P < 0.05), whereas it was positively correlated with podoplanin mRNA levels (r = 0.468, P < 0.05) and proteinuria (r = 0.585, P = 0.001).

Loss of slit protein nephrin is associated with reduced antioxidant superoxide dismutase expression in podocytes shed from women with preeclampsia.

To test the hypothesis that oxidative stress contributes to kidney podocyte injury in preeclampsia, we specifically examined expression and distribution of antioxidant CuZn-SOD with nephrin and podoplanin in shed podocytes from women with preeclampsia.

We found that CuZn-SOD was localized at the front/outreach region of nephrin at the cell periphery (foot process areas) in control podocytes and expression of CuZn-SOD, nephrin, and podoplanin were all dislocated or lost in shed podocytes from preeclamptic patients.

We further tested oxidative stress-induced nephrin shedding in podocytes, in which AB 8/13 podocytes were cultured under lowered oxygen condition (2%O2 ) or treated with hypoxic mimicking agent cobalt chloride.

Our results showed that reduced nephrin and podoplanin expression were associated with downregulation of CuZn-SOD expression in podocytes when cells were cultured under lowered oxygen or hypoxic conditions.