Mutations in the Wilms' tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9.
Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. Approximately 10-25% of familial and sporadic cases are caused by mutations in NPHS2 (podocin). Mutations in exons 8 and 9 of the WT1 gene have been found in patients with isolated SRNS and in SRNS associated with Wilms' tumor (WT) or urogenital malformations. However, no large studies have been performed to date to examine whether WT1 mutations in isolated SRNS are restricted to exons 8 and 9. To address this question, we screened a worldwide cohort of 164 cases of sporadic SRNS for mutations in all 10 exons of the WT1 gene by multiplex capillary heteroduplex analysis and direct sequencing. NPHS2 mutations had been excluded by direct sequencing. Fifteen patients exhibited seven different mutations exclusively in exons 8 and 9 of WT1. Although it is possible that pathogenic mutations of WT1 may also reside in the introns, regions of the gene that were not able to be screened in this study, these data together with our previous results (Ruf et al.: Kidney Int 66: 564-570, 2004) indicate that screening of WT1 exons 8 and 9 in patients with sporadic SRNS is sufficient to detect pathogenic WT1 mutations and may open inroads into differential therapy of SRNS.
Mucha
Bettina
B
Department of Pediatrics, University of Michigan, Ann Arbor, 48109, USA.
Ozaltin
Fatih
F
Hinkes
Bernward G
BG
Hasselbacher
Katrin
K
Ruf
Rainer G
RG
Schultheiss
Michael
M
Hangan
Daniela
D
Hoskins
Bethan E
BE
Everding
Anne Schulze
AS
Bogdanovic
Radovan
R
Seeman
Thomas
T
Hoppe
Bernd
B
Hildebrandt
Friedhelm
F
D000595:Amino Acid Sequence; D001483:Base Sequence; D015331:Cohort Studies; D017931:DNA Primers; D005091:Exons; D005260:Female; D016162:Genes, Wilms Tumor; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009404:Nephrotic Syndrome / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D013256:Steroids / Q000494:pharmacology*
D017931:DNA Primers; D013256:Steroids