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

Edgar A. Otto, Bernhard Schermer, Tomoko Obara, John F. O'Toole, Karl S. Hiller, Adelheid M. Mueller, Rainer G. Ruf, Julia Hoefele, Frank Beekmann, Daniel Landau, John W. Foreman, Judith A. Goodship, Tom Strachan, Andreas Kispert, Matthias T. Wolf, Marie F. Gagnadoux, Hubert Nivet, Corinne Antignac, Gerd Walz, Iain A. DrummondThomas Benzing, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

453 Citations (Scopus)

Abstract

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 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 left-right axis determination.

Original languageEnglish (US)
Pages (from-to)413-420
Number of pages8
JournalNature Genetics
Volume34
Issue number4
DOIs
StatePublished - Aug 1 2003

Fingerprint

Cystic Kidney Diseases
Cilia
Polycystic Kidney Diseases
Tubulin
Mutation
Kidney
Genes
Situs Inversus
Phenotype
Zebrafish
Random Allocation
Chronic Kidney Failure
Nephronophthisis 2

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. / Otto, Edgar A.; Schermer, Bernhard; Obara, Tomoko; O'Toole, John F.; Hiller, Karl S.; Mueller, Adelheid M.; Ruf, Rainer G.; Hoefele, Julia; Beekmann, Frank; Landau, Daniel; Foreman, John W.; Goodship, Judith A.; Strachan, Tom; Kispert, Andreas; Wolf, Matthias T.; Gagnadoux, Marie F.; Nivet, Hubert; Antignac, Corinne; Walz, Gerd; Drummond, Iain A.; Benzing, Thomas; Hildebrandt, Friedhelm.

In: Nature Genetics, Vol. 34, No. 4, 01.08.2003, p. 413-420.

Research output: Contribution to journalArticle

Otto, EA, Schermer, B, Obara, T, O'Toole, JF, Hiller, KS, Mueller, AM, Ruf, RG, Hoefele, J, Beekmann, F, Landau, D, Foreman, JW, Goodship, JA, Strachan, T, Kispert, A, Wolf, MT, Gagnadoux, MF, Nivet, H, Antignac, C, Walz, G, Drummond, IA, Benzing, T & Hildebrandt, F 2003, 'Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination', Nature Genetics, vol. 34, no. 4, pp. 413-420. https://doi.org/10.1038/ng1217
Otto, Edgar A. ; Schermer, Bernhard ; Obara, Tomoko ; O'Toole, John F. ; Hiller, Karl S. ; Mueller, Adelheid M. ; Ruf, Rainer G. ; Hoefele, Julia ; Beekmann, Frank ; Landau, Daniel ; Foreman, John W. ; Goodship, Judith A. ; Strachan, Tom ; Kispert, Andreas ; Wolf, Matthias T. ; Gagnadoux, Marie F. ; Nivet, Hubert ; Antignac, Corinne ; Walz, Gerd ; Drummond, Iain A. ; Benzing, Thomas ; Hildebrandt, Friedhelm. / Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. In: Nature Genetics. 2003 ; Vol. 34, No. 4. pp. 413-420.
@article{bceb378912d14f11944570bda2a5a68c,
title = "Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination",
abstract = "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 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 left-right axis determination.",
author = "Otto, {Edgar A.} and Bernhard Schermer and Tomoko Obara and O'Toole, {John F.} and Hiller, {Karl S.} and Mueller, {Adelheid M.} and Ruf, {Rainer G.} and Julia Hoefele and Frank Beekmann and Daniel Landau and Foreman, {John W.} and Goodship, {Judith A.} and Tom Strachan and Andreas Kispert and Wolf, {Matthias T.} and Gagnadoux, {Marie F.} and Hubert Nivet and Corinne Antignac and Gerd Walz and Drummond, {Iain A.} and Thomas Benzing and Friedhelm Hildebrandt",
year = "2003",
month = "8",
day = "1",
doi = "10.1038/ng1217",
language = "English (US)",
volume = "34",
pages = "413--420",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

AU - Otto, Edgar A.

AU - Schermer, Bernhard

AU - Obara, Tomoko

AU - O'Toole, John F.

AU - Hiller, Karl S.

AU - Mueller, Adelheid M.

AU - Ruf, Rainer G.

AU - Hoefele, Julia

AU - Beekmann, Frank

AU - Landau, Daniel

AU - Foreman, John W.

AU - Goodship, Judith A.

AU - Strachan, Tom

AU - Kispert, Andreas

AU - Wolf, Matthias T.

AU - Gagnadoux, Marie F.

AU - Nivet, Hubert

AU - Antignac, Corinne

AU - Walz, Gerd

AU - Drummond, Iain A.

AU - Benzing, Thomas

AU - Hildebrandt, Friedhelm

PY - 2003/8/1

Y1 - 2003/8/1

N2 - 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 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 left-right axis determination.

AB - 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 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 left-right axis determination.

UR - http://www.scopus.com/inward/record.url?scp=0041592700&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0041592700&partnerID=8YFLogxK

U2 - 10.1038/ng1217

DO - 10.1038/ng1217

M3 - Article

C2 - 12872123

AN - SCOPUS:0041592700

VL - 34

SP - 413

EP - 420

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 4

ER -