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/NPHP7C175R point mutation abolished the nuclear localization of GLIS2/NPHP7. Forced nuclear import did not rescue the transcriptional defects of GLIS2/NPHP7C175R, indicating additional defects as DNA-binding protein. We further observed that wild type, but not GLIS2/NPHP7C175R, 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.
Highlights
Nephronophthisis (NPH) is a rare autosomal recessive disease associated with chronic kidney disease and renal failure as well as multiple extrarenal manifestations
As small amounts of GLIS2/NPHP7C175R were present in the nucleus (Figure 2b), we addressed the possibility that the mutation, located within the first zinc-finger affects the transcriptional function of GLIS2/NPHP7
Given the lack of NPH-typical extrarenal manifestations in the patient with the GLIS2/NPHP7C175R mutation, we hypothesized that studying this point mutation might reveal additional insights into the function and structural requirements of GLIS2/NPHP7
Summary
Nephronophthisis (NPH) is a rare autosomal recessive disease associated with chronic kidney disease and renal failure as well as multiple extrarenal manifestations. Most nephrocystins appear to form large protein networks at the basal body and the transition zone to execute ciliary functions.[1,2] NPH type VII represents an exception: GLIS2/NPHP7 is a zinc-finger protein that recognizes the DNA motif (G/C)TGGGGGGT(A/C), acting as a transcriptional repressor or co-activator.[3] GLIS2/NPHP7 knockout mice suggest that this protein suppresses genes associated with mesenchymal characteristics, maintaining an epithelial phenotype.[4] GLIS2/NPHP7 inhibits Snai[1] and Wnt[4] by binding cis-acting regulatory sequences, thereby antagonizing hedgehog and Wnt signaling.[5] In the absence of GLIS2/NPHP7, genes that facilitate an epithelial-to-mesenchymal transition are increasingly expressed, promoting fibrosis and renal failure.[4,5,6] Recently, a GLIS2/NPHP7 c.523T4C mutation in both the alleles of Glis[2], resulting in a C175R substitution at the beginning of the first zinc-finger domain of GLIS2/NPHP7, was identified in a patient with end-stage renal disease,[7] suggesting that this point mutation was responsible for the NPH manifestation. As the differentiation between disease-relevant point mutations and irrelevant amino-acid substitutions represents a major challenge in determining the significance of novel human mutations, we decided to study the GLIS2/NPHP7C175R mutant in more detail
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