Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal recessive disorder that is caused by mutations in the recently discovered nephrin gene, NPHS1 (AF035835). The disease, which belongs to the Finnish disease heritage, exists predominantly in Finland, but many cases have been observed elsewhere in Europe and North America. The nephrin gene consists of 29 exons spanning 26 kb in the chromosomal region 19q13.1. In the present study, the genomic structure of the nephrin gene was analyzed, and 35 NPHS1 patients were screened for the presence of mutations in the gene. A total of 32 novel mutations, including deletions; insertions; nonsense, missense, and splicing mutations; and two common polymorphisms were found. Only two Swedish and four Finnish patients had the typical Finnish mutations: a 2-bp deletion in exon 2 (Fin(major)) or a nonsense mutation in exon 26 (Fin(minor)). In seven cases, no mutations were found in the coding region of the NPHS1 gene or in the immediate 5'-flanking region. These patients may have mutations elsewhere in the promoter, in intron areas, or in a gene encoding another protein that interacts with nephrin.
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We thank Petra Huuhka, Maire Jarva, Mervi Matero, Beryl Greenberg, and the staff of the Clinical Research Center at the University of Minnesota for their excellent technical assistance, and we thank all the clinicians and NPHS1 families who contributed to this work. We are grateful for control samples obtained from members of the non-Finnish personnel at the University of Oulu. This work was supported in part by grants from the Sigrid Juselius Foundation, the Academy of Finland, the Swedish Medical Research Council, and the Hedlund Foundation. Studies of the North American families were supported in part by grant MO1-RR00400 from the National Center for Research Resources. C.E.K. received support from the National Institutes of Health (AI-10704-36). Work at Lawerence Livermore National Laboratory was supported by the US Department of Energy under contract W-7405-ENG-48.