title: The C175R mutation alters nuclear localization and transcriptional activity of the nephronophthisis NPHP7 gene product.
abstract: Nephronophthisis (NPH) is a rare autosomal ciliopathy, but the leading cause for hereditary end-stage renal disease in children. Most NPH family members form large protein networks, which appear to participate in structural elements of the cilium and/or function to restrict access of molecules to the ciliary compartment. The zinc-finger protein GLIS2/NPHP7 represents an exception as it has been implicated in transcriptional regulation; only two families with GLIS2/NPHP7 mutations and typical NPH manifestations have been identified so far. We describe here that the recently identified GLIS2/NPHP7(C175R) point mutation abolished the nuclear localization of GLIS2/NPHP7. Forced nuclear import did not rescue the transcriptional defects of GLIS2/NPHP7(C175R), indicating additional defects as DNA-binding protein. We further observed that wild type, but not GLIS2/NPHP7(C175R), prevented the cyst formation caused by depletion of nphp7 in zebrafish embryos. Taken together, our findings indicate that the C175R mutation affects both localization and function of GLIS2/NPHP7, supporting a role of this mutation in NPH, but questioning the direct involvement of GLIS2/NPHP7 in ciliary functions.
authors.affiliation: Renal Division, Freiburg University Medical Center, Freiburg, Germany.
authors.forename: Haribaskar
authors.initials: H
authors.lastname: Ramachandran
authors.affiliation: Renal Division, Freiburg University Medical Center, Freiburg, Germany.
authors.forename: Toma A
authors.initials: TA
authors.lastname: Yakulov
authors.affiliation: Renal Division, Freiburg University Medical Center, Freiburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Engel
authors.affiliation: Renal Division, Freiburg University Medical Center, Freiburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Müller
authors.affiliation: Renal Division, Freiburg University Medical Center, Freiburg, Germany.|Center for Biological Signaling Studies (BIOSS), Albertstraße 19, Freiburg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D011485:Protein Binding; D015533:Transcriptional Activation; D015027:Zebrafish
chemical_list: C447919:GLIS2 protein, human; D051741:Kruppel-Like Transcription Factors