NDT Advance Access originally published online on May 23, 2008
Nephrology Dialysis Transplantation 2008 23(11):3527-3533; doi:10.1093/ndt/gfn271
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Thirteen novel NPHS1 mutations in a large cohort of children with congenital nephrotic syndrome
1 Departments of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI 2 Division of Nephrology, Department of Pediatrics, Children's Health Center, Duke University Medical Center, Duke University, Durham, NC, USA 3 Kinder-und Jugendklinik, Universität Erlangen-Nürnberg, Erlangen, Germany 4 Department of Pediatrics, Unit of Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey
Correspondence and offprint requests to: Friedhelm Hildebrandt, University of Michigan Health System, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5646, USA. Tel: +1-734-615-7285; Fax: +1-734-615-1386, -7770; E-mail: fhilde{at}umich.edu
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Abstract |
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Background. Congenital nephrotic syndrome (CNS) is de- fined as nephrotic syndrome that manifests at birth or within the first 3 months of life. Most patients develop end-stage renal disease (ESRD) within 2 to 3 years of life. CNS of the Finnish-type (CNF) features a rather specific renal histology and is caused by recessive mutations in the NPHS1 gene encoding nephrin, a major structural protein of the glomerular slit-diaphragm. So far, more than 80 different mutations of NPHS1 causing CNF have been published.
Methods. Here, we performed mutation analysis of NPHS1 by exon sequencing in a worldwide cohort of 32 children with CNS from 29 different families.
Results. Sixteen of the 29 families (55%) were found to have two disease-causing alleles in NPHS1. Two additional patients had a single heterozygous mutation in NPHS1. Thirteen of a total of 20 different mutations detected were novel (65%). These were five missense mutations, one nonsense mutation, three deletions, one insertion and three splice-site mutations.
Conclusion. Our data expand the spectrum of known NPHS1 mutations by >15% in a worldwide cohort. Surprisingly, two patients with disease-causing mutations showed a relatively mild phenotype, as one patient had a partial remission with steroid treatment and one patient had normal renal function 1 year after the onset of disease. The increased number of known mutations will facilitate future studies into genotype/phenotype correlations.
Keywords: CNS; novel mutations; NPHS1
* Members of the APN Study Group: A. Noyan; A. Bakkaloglu; S. Spranger; S. Briese; D. Müller; U. Querfeld; G. Reusz; R. Bogdanovic; B. Beck; B. Hoppe; M. T. F. Wolf; K. Dittrich; J. Dötsch; C. Plank; E.-M. Rüth; W. Rascher; P. Hoyer; M. Schröder; M. Brandis; A. Fuchshuber; M. Pohl; C. v. Schnakenburg; C. Mache; F. Schäfer; T. Knüppel; O. Mehls; B. Tönshoff; D. Wenning; M. Kemper; D. E. Müller-Wiefel; J. H. H. Ehrich; G. Offner; M. Barenbrock; T. Jungraithmayr; B. Zimmerhackl; J. Misselwitz; S. Wygoda; D. Böckenhauer; M. Schuhmacher; M. Benz; M. Griebel; J. Höfele; L. Weber; H. Fehrenbach; M. Bulla; E. Kuwertz-Bröcking; A. Schulze Everding; M. Shenoy; L. Patzer; T. Seeman; A. Gianviti; G. Rizzoni; O. Amon; C. Licht; J. Mühleder; G. Laube; T. Neuhaus; T. Stuckert.
Received for publication: 12. 2.08
Accepted in revised form: 18. 4.08