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PMID: 12872123 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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 ·2003-08-00 ·Pages 413-20

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

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 beta-tubulin, a main component of primary cilia. We show that nephrocystin, inversin and beta-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 beta-tubulin connect pathogenetic aspects of NPHP to PKD, to primary cilia function and to left-right axis determination.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Base Sequence Body Patterning/genetics,physiology Child Cilia/physiology Cytoskeletal Proteins DNA/genetics Female Gene Targeting Humans Kidney Diseases, Cystic/genetics,physiopathology Male Membrane Proteins Molecular Sequence Data Mutation Polycystic Kidney, Autosomal Recessive/genetics Proteins/genetics,physiology Situs Inversus/embryology,genetics Transcription Factors Tubulin/physiology Zebrafish/embryology,genetics
Chemicals
Adaptor Proteins, Signal Transducing Cytoskeletal Proteins INVS protein, human Membrane Proteins NPHP1 protein, human NPHP4 protein, human Proteins Transcription Factors Tubulin DNA
Authors & Affiliations
22 authors, click to expand affiliations / ORCID
Otto Edgar A
Department of Pediatrics, 8220C MSRB III, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, Michigan 48109, USA.
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
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1061-4036
DOI
10.1038/ng1217
Published
2003-08-00
Pages
413-20
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3732175
Subset
IM
Grants
NIDDK NIH HHS · R01 DK078209 · United States
NIDDK NIH HHS · R21 DK069604 · United States
Databases
GENBANK
AF465261
OMIM
256100, 606966
RefSeq
NM_010569, NM_014425, NT_008470
Corrections
CommentIn
PMID: 12923538
External Links
PubMed source DOI: 10.1038/ng1217 PMC Full Text View journal details
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