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The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin

A Corrigendum to this article was published on 01 November 2002

Abstract

Nephronophthisis, the most common genetic cause of chronic renal failure in children, is a progressive tubulo-interstitial kidney disorder that is inherited as an autosomal recessive trait. The disease is characterized by polyuria, growth retardation and deterioration of renal function during childhood or adolescence. The most prominent histological features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts1. Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (Senior–Løken syndrome)2,3 and ocular motor apraxia (Cogan syndrome)4. Three loci are associated with the juvenile, infantile and adolescent forms, on chromosomes 2q13 (NPHP1; refs 5,6), 9q22 (NPHP2; ref. 7) and 3q21 (NPHP3; ref. 8), respectively. NPHP1, the only gene identified so far, encodes nephrocystin9,10, which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion11,12,13. Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 (ref. 14). We carried out haplotype analysis of families affected with nephronophthisis that were not linked to the NPHP1, NPHP2 or NPHP3 loci, using markers covering this region. This allowed us to reduce the NPHP4 interval to a one centimorgan interval between D1S2795 and D1S2870, which contains six genes. We identified five different mutations in one of these genes, designated NPHP4, in unrelated individuals with nephronophthisis. The NPHP4 gene encodes a 1,250–amino acid protein of unknown function that we named nephrocystin-4. We demonstrated the interaction of nephrocystin-4 with nephrocystin suggesting that these two proteins participate in a common signaling pathway.

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Figure 1: Families affected with nephronophthisis linked to the NPHP4 locus on chromosome 1p36.
Figure 2: Map of the human NPHP4 region and structure of full-length NPHP4.
Figure 3: Northern-blot analysis of NPHP4 expression.
Figure 4: ClustalW multiple-protein alignment of human nephrocystin-4 with mouse (Nphp4) and C. elegans (R13H4.1) orthologs.
Figure 5: Interaction between nephrocystin-4 and nephrocystin in mammalian cells.

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Notes

  1. NOTE: Errors appeared in the AOP and print versions of this article due to a DNA sequence analysis error. We inadvertantly deleted two cytosines in the previously named exon -4. This masked a methionine codon located 176 amino acids upstream of the previously reported initiation codon. Correction of this error indicates that NPHP4 contains four additional coding exons, and the protein nephrocystin-4 is composed of 1,426 amino acids instead of 1,250. The exons should be renumbered as follows: exon -5 becomes exon 1, the initiation codon is in exon 2 and the last exon is exon 30. The designations of all the mutations in Table 1 have changed. Table 1 now appears correctly in the HTML version. Per company policy, the PDF version will be amended when the corrigendum is published in an upcoming issue.

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Acknowledgements

We thank S. Lyonnet for helpful discussions, R. Hervé and F. Benessy for their technical assistance and Y. Deris for his photographic assistance. This work was supported by the Association Française contre les Myopathies, the Association pour l'Utilisation du Rein Artificiel, the Fondation pour la Recherche Médicale (to G.M.) and the Ministère de l'Education Nationale, de la Recherche et de la Technologie (to G.M.).

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Correspondence to Corinne Antignac.

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Mollet, G., Salomon, R., Gribouval, O. et al. The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat Genet 32, 300–305 (2002). https://doi.org/10.1038/ng996

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