Abstract
Juvenile nephronophthisis (NPH), an autosomal recessive cystic kidney disease, is the primary genetic cause of chronic renal failure in children. About two thirds of patients with NPH carry a large homozygous deletion at the gene locus NPH1 on 2q13. We here identify a novel gene, NPHP1, which extends over most of this common deletion. The 4.5–kb transcript encodes a protein with an SH3 domain, which is highly conserved throughout evolution. The 11–kb interval between the 3′ end of NPHP1 and an inverted repeat containing the distal deletion breakpoint was found to contain the first exon of a second gene, MALL. In patients with a hemizygous deletion of the NPH1 region, additional point mutations were found in NPH1 but not in MALL.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fanconi, G. et al. Familiäre juvenile Nephronophthise. Helv. Paediatr. Acta 6, 1–49 (1951).
Smith, C.H. & Graham, J.B. Congenital medullary cysts of the kidneys with severe refractory anemia. Am. J. Dis. Child. 69, 369–377 (1945).
Kleinknecht, C. & Habib, R. Nephronophthisis. in Textbook of Clinical Nephrology (eds Cameron, J.C., Davison, A.M., Grünfeld, J.P., Kers, K.N.S. & Ritz, E.) 2188–2197 (Oxford University Press, Oxford, (1992).
Waldherr, R., Lennert, T., Weber, H.P., Fodish, H.J., & Schärer, K. The nephronophthisis complex: a clinicopathologic study in children. Virchows Archiv. A Pathol. Anat. Histopathol. 394, 235–254 (1982).
Antignac, C. et al. A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p. Nature Genet. 3, 342–345 (1993).
Hildebrandt, F. et al. Mapping of a gene for familial juvenile nephronophthisis: Refining the map and defining flanking markers on chromosome 2. Am. J. Hum. Genet. 53, 1256–1261 (1993).
Medhioub, M. et al. Refined mapping of a gene (NPH1) causing familial (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity. Genomics 22, 296–301 (1994).
Hildebrandt, F., Singh-Sawhney, I., Schnieders, B., Papenfuss, T. & Brandis, M. Refined genetic mapping of a gene for familial juvenile nephronophthisis (NPH1) and physical mapping of linked markers. Genomics 25, 360–364 (1995).
Hildebrandt, F. et al. Physical mapping of the gene for juvenile nephronophthisis (NPH1) by construction of a complete YAC contig of 7 Mb on chromosome 2q13. Cytogenet Cell Genet. 73, 235–239 (1996).
Konrad, M. et al. 11 Mb YAC-based contig spanning the familial juvenile nephronophthisis region (NPH1) located on chromosome 2q. Genomics 30, 514–520 (1995).
Konrad, M. et al. Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum. Mol. Genet. 5, 367–371 (1996).
Hildebrandt, F. et al. Molecular genetic identification of families with juvenile nephronophthisis 1: Rate of progression to renal failure. Kidney Int. 51, 261–269 (1997).
Hildebrandt, F., Jungers, P. & Grunfeld, J.P. Medullary cystic and medullary sponge renal disorders. in Diseases of the Kidney (eds Schrier, W. B. & Gottschalk, C.) 499–520 (Little, Brown, Boston, (1996).
Lennon, G., Auffray, C., Polymeropoulos, M. & Soares, M.B. The I.M.A.G.E. consortium: an integrated molecular analysis of genomes and their expression. Genomics 33, 151–152 (1996).
Shaw, G. & Kamen, R. A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46, 659–667 (1986).
Marx, J. Forging a path to the nucleus. Science 260, 1588–1590 (1993).
Rancaño, C., Rubio, T. & Alonso, M.A. Alternative splicing of human T-cell-specific MAL mRNA and its correlation with the exon/intron organization of the gene. Genomics 21, 447–450 (1994).
Meindl, A. et al. A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nature Genet. 13, 35–42 (1996).
Nothwang, H.G. et al. Molecular cloning of the interleukin-1 gene cluster: construction of an integrated YAC, PAC and partial transcriptional map in the region of chromosome 2q13. Genomics (in the press).
Chowdhury, K. One step ‘miniprep’ method for the isolation of plasmid DNA. Nucleic Acids Res. 19, 2792 (1991).
Olson, M., Hood, L., Cantor, C. & Botstein, D. A common language for physical mapping of the human genome. Science 245, 1434–1435 (1989).
International Collaborative Study Group for Bartter-like Syndromes. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. Hum. Mol. Genet. 6, 17–26 (1997).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hildebrandt, F., Otto, E., Rensing, C. et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 17, 149–153 (1997). https://doi.org/10.1038/ng1097-149
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1097-149
This article is cited by
-
Transport and barrier mechanisms that regulate ciliary compartmentalization and ciliopathies
Nature Reviews Nephrology (2024)
-
Nephronophthisis: a pathological and genetic perspective
Pediatric Nephrology (2023)
-
MALL, a membrane-tetra-spanning proteolipid overexpressed in cancer, is present in membraneless nuclear biomolecular condensates
Cellular and Molecular Life Sciences (2022)
-
Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes
Scientific Reports (2022)
-
Atypical histological abnormalities in an adult patient with nephronophthisis harboring NPHP1 deletion: a case report
BMC Nephrology (2021)