A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1

Hildebrandt, Friedhelm; Otto, Edgar A.; Rensing, Christopher; Nothwang, Hans Gerd; Vollmer, Martin; Adolphs, Jörn; Hanusch, Helge; Brandis, M.

doi:10.1038/ng1097-149

Cited by 328 publications

(261 citation statements)

References 17 publications

Supporting

Mentioning

250

Contrasting

Unclassified

Order By: Relevance

“…The role of nephrocystin in extrarenal manifestations remains poorly understood. The 11 kb interval between the 3 0 end of NPHP1 and an inverted repeat containing the distal deletion breakpoint was found to contain the first exon of a second gene, MALL [20]. Although the detail of the MALL gene function has not been clarified, recent report suggested the involvement of the age-related macular degeneration (AMD) [21].…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic characteristics of Japanese nephronophthisis patients

et al. 2015

View full text Add to dashboard Cite

Background Nephronophthisis (NPH) accounts for 4-5 % of end-stage renal disease occurring in childhood. Method We investigated the clinical context and characteristics of renal and extrarenal symptoms, as well as the NPHP genes, in 35 Japanese patients with clinical and histologic features suggesting NPH. Results NPH occurred fairly uniformly throughout Japan irrespective of region or gender. In three families, NPH affected siblings. The median age of patients was 12.5 years. Renal abnormalities attributable to NPH discovered through mass screening, such as urine tests in school. However, NPH accounted for less than 50 % of children with abnormal findings, including incidentally discovered renal dysfunction during evaluation of extrarenal symptoms or during routine check-ups. Typical extrarenal manifestations leaded to discovery including anemia and delayed physical development. The urine often showed low gravity specific density and low molecular weight proteinuria. Frequent renal histologic findings included cystic dilation of tubules, mainly in the medulla, and irregularity of tubular basement membranes. Genetically abnormalities of NPHP1 were not common, with large deletions frequently noted. Compound heterozygotes showing single abnormalities in each of NPHP1, NPHP3, and NPHP4 were observed. Conclusions Our findings resemble those reported in Western populations.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical and genetic characteristics of Japanese nephronophthisis patients

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In the early 1990s, the first gene locus for NPH to human chromosome 2q12-q13 was mapped, and recently, 3 new genes were discovered. [2][3][4][5] Interestingly, NPH genes colocalize with PKD genes to the primary cilium. 4,5,[40][41][42][43][44] Previously thought to be vestigial cellular organelles, primary cilia function as flow-sensitive mechanosensors.…”

Section: Uromodulin and Medullary Cystic Kidney Disease Type 2: The Umentioning

confidence: 97%

“…1 Recent advances in the field of molecular genetics provide the opportunity for revision of the pathogenic aspects of renal cystic diseases and put forth the basis for a renewed classification. Starting from 1997, causative mutations in 4 genes for NPH (NPHP1, NPHP2, NPHP3, and NPHP4) have been identified, [2][3][4][5] and based on functional genomics, some links between the NPH family and PKD genes were described.…”

mentioning

confidence: 99%

Uromodulin storage diseases: Clinical aspects and mechanisms

Scolari

Caridi

Rampoldi

et al. 2004

American Journal of Kidney Diseases

125

100

View full text Add to dashboard Cite

• The recent discovery of mutations in the uromodulin gene (UMOD) in patients with medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD) provides the opportunity for a revision of pathogenic aspects and puts forth the basis for a renewed classification. This review focuses on clinical, pathological, and cell biology advances in UMOD-related pathological states, including a review of the associated clinical conditions described to date in the literature. Overall, 31 UMOD mutations associated with MCKD2 and FJHN (205 patients) and 1 mutation associated with GCKD (3 patients) have been described, with a cluster at exons 4 and 5. Most are missense mutations causing a cysteine change in uromodulin sequence. No differences in clinical symptoms between carriers of cysteine versus polar residue changes have been observed; clinical phenotypes invariably are linked to classic MCKD2/FJHN. A common motif among all reports is that many overlapping symptoms between MCKD2 and FJHN are present, and a separation between these 2 entities seems unwarranted or redundant. Cell experiments with mutant variants indicated a delay in intracellular maturation and export dynamics, with consequent uromodulin storage within the endoplasmic reticulum (ER). Patchy uromodulin deposits in tubule cells were found by means of immunohistochemistry, and electron microscopy showed dense fibrillar material in the ER. Mass spectrometry showed only unmodified uromodulin in urine of patients with UMOD mutations. Lack of uromodulin function(s) is associated with impairments in tubular function, particularly the urine-concentrating process, determining water depletion and hyperuricemia. Intracellular uromodulin trapping within the ER probably has a major role in determining tubulointerstitial fibrosis and renal failure. We propose the definition of uromodulin storage diseases for conditions with proven UMOD mutations. Am J Kidney Dis 44:987-999.

show abstract

“…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 .…”

mentioning

confidence: 99%

“…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.…”

mentioning

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1

Cited by 328 publications

References 17 publications

Clinical and genetic characteristics of Japanese nephronophthisis patients

Clinical and genetic characteristics of Japanese nephronophthisis patients

Uromodulin storage diseases: Clinical aspects and mechanisms

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

Contact Info

Product

Resources

About