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. Drummond; Thomas Benzing; Friedhelm Hildebrandt

doi:10.1038/ng1217

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

548 Scopus citations

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 language	English
Pages (from-to)	413-420
Number of pages	8
Journal	Nature Genetics
Volume	34
Issue number	4
DOIs	https://doi.org/10.1038/ng1217
State	Published - 1 Aug 2003
Externally published	Yes

Funding

Funders	Funder number
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases	R21DK069604
Deutsche Forschungsgemeinschaft

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Otto, E. A., Schermer, B., Obara, T., O'Toole, J. F., Hiller, K. S., Mueller, A. M., Ruf, R. G., Hoefele, J., Beekmann, F., Landau, D., Foreman, J. W., Goodship, J. A., Strachan, T., Kispert, A., Wolf, M. T., Gagnadoux, M. F., Nivet, H., Antignac, C., Walz, G., ... 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, 34(4), 413-420. https://doi.org/10.1038/ng1217

@article{2fcf56a49fe44f38a88343faa0e4f41e,

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",

note = "Funding Information: We thank the affected individuals and their families for participation, J. Robillard for discussion, R.H. Lyons and A. Imm for large-scale sequencing and P. Cochat for contribution of clinical data on individuals A8 and A10. F.H., G.W. and T.B. are supported by Sonderforschungsbereich 592 of the German Research Foundation and by DFG grants to T.B. and G.W.; I.A.D. and T.O. are supported by grants from the US National Institutes of Health to I.A.D.",

year = "2003",

month = aug,

day = "1",

doi = "10.1038/ng1217",

language = "אנגלית",

volume = "34",

pages = "413--420",

journal = "Nature Genetics",

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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

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

N1 - Funding Information: We thank the affected individuals and their families for participation, J. Robillard for discussion, R.H. Lyons and A. Imm for large-scale sequencing and P. Cochat for contribution of clinical data on individuals A8 and A10. F.H., G.W. and T.B. are supported by Sonderforschungsbereich 592 of the German Research Foundation and by DFG grants to T.B. and G.W.; I.A.D. and T.O. are supported by grants from the US National Institutes of Health to I.A.D.

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.

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JF - Nature Genetics

IS - 4

ER -

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

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UN SDGs

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