The Nephronophthisis Complex; a Clinicopathologic Study

Waldherr, Rüdiger; Lennert, Thomas; Weber, H.P.; Födisch, H. J.; Michalk, Dietrich; Schärer, K

doi:10.1007/978-3-642-68144-8_2

Cited by 42 publications

(69 citation statements)

References 10 publications

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“…Later, cysts appear at the corticomedullary junction within kidneys of normal or slightly reduced size ( Figure 1, A and B) (9). Renal histology reveals a characteristic triad of tubular basement membrane disruption, tubulointerstitial nephropathy, and corticomedullary cysts ( Figure 1C) (10,11). In NPHP, cysts arise from the corticomedullary junction of the kidneys ( Figure 1, A and B).…”

Section: Nephronophthisis: a Frequent Genetic Cause Of Kidney Failurementioning

confidence: 99%

“…This includes NPHP variants with extrarenal manifestations (4). NPHP has previously been grouped together with the clinical entity of medullary cystic kidney disease (MCKD) (6,10) because of similarities of clinical and pathologic features (12). Both NPHP and MCKD feature corticomedullary cysts in kidneys of normal or slightly reduced size.…”

Section: Nephronophthisis: a Frequent Genetic Cause Of Kidney Failurementioning

confidence: 99%

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Nephronophthisis-Associated Ciliopathies

Hildebrandt

Zhou

2007

Journal of the American Society of Nephrology

350

314

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Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, represents the most frequent genetic cause of end-stage kidney disease in the first three decades of life. Contrary to polycystic kidney disease, NPHP shows normal or diminished kidney size, cysts are concentrated at the corticomedullary junction, and tubulointerstitial fibrosis is dominant. NPHP can be associated with retinitis pigmentosa (Senior-Løken syndrome), liver fibrosis, and cerebellar vermis aplasia (Joubert syndrome) in approximately 10% of patients. Positional cloning of six novel genes (NPHP1 through 6) as mutated in NPHP and functional characterization of their encoded proteins have contributed to the concept of "ciliopathies." It has helped advance a new unifying theory of cystic kidney diseases. This theory states that the products of all genes that are mutated in cystic kidney diseases in humans, mice, or zebrafish are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, osmotic, and other stimuli to mechanisms of cell-cycle control and epithelial cell polarity. The ciliary theory explains the multiple organ involvement in NPHP regarding retinitis pigmentosa, liver fibrosis, ataxia, situs inversus, and mental retardation. Mutations in NPHP genes cause defects in signaling mechanisms, including the noncanonical Wnt signaling pathway. The "ciliopathy" NPHP thereby is caused by defects in tissue differentiation and maintenance as a result of impaired processing of extracellular cues. Nephrocystins, the proteins that are encoded by NPHP genes, are highly conserved in evolution. Positional cloning of additional causative genes of NPHP will elucidate further signaling mechanisms that are involved, thereby establishing therapeutic approaches using animal models in mouse, zebrafish, and Caenorhabditis elegans.

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Section: Nephronophthisis: a Frequent Genetic Cause Of Kidney Failurementioning

confidence: 99%

Section: Nephronophthisis: a Frequent Genetic Cause Of Kidney Failurementioning

confidence: 99%

Nephronophthisis-Associated Ciliopathies

Hildebrandt

Zhou

2007

Journal of the American Society of Nephrology

350

314

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“…Approval for human subjects' research was obtained from the University of Michigan Institutional Review Board and relevant local review boards. NPHP-related disorder was diagnosed by (pediatric) nephrologists on the basis of standardized clinical 32 and renal ultrasonographic criteria. 4 Renal biopsy specimens were evaluated by renal pathologists.…”

Section: Research Participantsmentioning

confidence: 99%

Mutation of the Mg2+ Transporter SLC41A1 Results in a Nephronophthisis-Like Phenotype

Hurd

Otto

Mishima

et al. 2013

Journal of the American Society of Nephrology

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Nephronophthisis (NPHP)-related ciliopathies are recessive, single-gene disorders that collectively make up the most common genetic cause of CKD in the first three decades of life. Mutations in 1 of the 15 known NPHP genes explain less than half of all cases with this phenotype, however, and the recently identified genetic causes are exceedingly rare. As a result, a strategy to identify single-gene causes of NPHP-related ciliopathies in single affected families is needed. Although whole-exome resequencing facilitates the identification of disease genes, the large number of detected genetic variants hampers its use. Here, we overcome this limitation by combining homozygosity mapping with whole-exome resequencing in a sibling pair with an NPHP-related ciliopathy. Whole-exome capture revealed a homozygous splice acceptor site mutation (c.698G.T) in the renal Mg 2+ transporter SLC41A1. This mutation resulted in skipping of exon 6 of SLC41A1, resulting in an in-frame deletion of a transmembrane helix. Transfection of cells with wild-type or mutant SLC41A1 revealed that deletion of exon 6 completely blocks the Mg 2+ transport function of SLC41A1. Furthermore, in normal human kidney tissue, endogenous SLC41A1 specifically localized to renal tubules situated at the corticomedullary boundary, consistent with the region of cystogenesis observed in NPHP and related ciliopathies. Last, morpholino-mediated knockdown of slc41a1 expression in zebrafish resulted in ventral body curvature, hydrocephalus, and cystic kidneys, similar to the effects of knocking down other NPHP genes. Taken together, these data suggest that defects in the maintenance of renal Mg 2+ homeostasis may lead to tubular defects that result in a phenotype similar to NPHP.

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“…Causative mutations in two genes (NPHP1 and NPHP4) have been identified by positional cloning [4][5][6][7] . There is considerable interest in identifying genes associated with NPHP because its most prominent feature is development of renal interstitial fibrosis 8 , which in chronic renal disease of all origin represents the pathogenic event correlated most strongly to loss of renal function 9 . As little was known about the pathogenesis of NPHP, positional cloning was used to identify a new gene, NPHP1, mutations in which cause NPHP1 (OMIM 256100; refs.…”

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confidence: 99%

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

et al. 2003

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Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, leads to chronic renal failure in children. The genes mutated in NPHP1 and NPHP4 have been identified, and a gene locus associated with infantile nephronophthisis (NPHP2) was mapped. The kidney phenotype of NPHP2 combines clinical features of NPHP and polycystic kidney disease (PKD). Here, we identify inversin (INVS) as the gene mutated in NPHP2 with and without situs inversus. We show Correspondence should be addressed to F.H. (fhilde@umich.edu). 12 These authors contributed equally to this work 13 These authors contributed equally to this work GenBank accession numbers. INVS cDNA, NM_014425; Invs cDNA, NM_010569; invs cDNA, AF465261; INVS in chromosome 9 genome contig, NT_008470.URLs. Additional information is available at http://danio.mgh.harvard.edu/blast/blast.html. Note: Supplementary information is available on the Nature Genetics website. Competing Interests Statement:The authors declare that they have no competing financial interests. NIH Public AccessAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2013 August 02. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript molecular interaction of inversin with nephrocystin, the product of the gene mutated in NPHP1 and interaction of nephrocystin with β-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and β-tubulin colocalize to primary cilia of renal tubular cells. Furthermore, we produce a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of invs expression in zebrafish. The interaction and colocalization in cilia of inversin, nephrocystin and β-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to leftright axis determination.NPHP, an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal failure in children and young adults [1][2][3] . Causative mutations in two genes (NPHP1 and NPHP4) have been identified by positional cloning [4][5][6][7] . There is considerable interest in identifying genes associated with NPHP because its most prominent feature is development of renal interstitial fibrosis 8 , which in chronic renal disease of all origin represents the pathogenic event correlated most strongly to loss of renal function 9 . As little was known about the pathogenesis of NPHP, positional cloning was used to identify a new gene, NPHP1, mutations in which cause NPHP1 (OMIM 256100; refs. 4,5). It encodes a novel docking protein, nephrocystin [10][11][12][13] , that interacts with components of cell-cell and cell-matrix signaling, such as focal adhesion kinase 2, tensin, p130Cas and filamin, and with nephrocystin-4 or nephroretinin, the product of NPHP4, mutations in which cause NPHP4 (OMIM 606966; refs. 6,7). Identification of the genes NPHP1 and NPHP4, which are conserved in evolution including in the nematode Caenorhabditis elegans, offered new insights into mechanisms of cell-cell and cell-matrix signaling...

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The Nephronophthisis Complex; a Clinicopathologic Study

Cited by 42 publications

References 10 publications

Nephronophthisis-Associated Ciliopathies

Nephronophthisis-Associated Ciliopathies

Mutation of the Mg2+ Transporter SLC41A1 Results in a Nephronophthisis-Like Phenotype

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

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