Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome.
BACKGROUND
Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant nephrotic syndrome (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes for end-stage renal disease (ESRD) in the first two decades of life. Sporadic mutations in the Wilms' tumor suppressor gene WT1 have been found to be present in patients with SRNS in association with Wilms' tumor (WT) and urinary or genital malformations, as well as in patients with isolated SRNS.


METHODS
To further evaluate the incidence of WT1 mutations in patients with NS we performed mutational analysis in 115 sporadic cases of SRNS and in 110 sporadic cases of steroid-sensitive nephrotic syndrome (SSNS) as a control group. Sixty out of 115 (52%) patients with sporadic SRNS were male, 55/115 (48%) were female. Sex genotype was verified by haplotype analysis. Mutational analysis was performed by direct sequencing and by denaturing high-performance liquid chromatography (DHPLC).


RESULTS
Mutations in WT1 were found in 3/60 (5%) male (sex genotype) cases and 5/55 (9%) female (sex genotype) cases of sporadic SRNS, and 0/110 (0%) sporadic cases of SSNS. One out of five female patients with mutations in WT1 developed a WT, 2/3 male patients presented with the association of urinary and genital malformations, 1/3 male patients presented with sexual reversal (female phenotype) and bilateral gonadoblastoma, and 4/5 female patients presented with isolated SRNS.


CONCLUSIONS
According to the data acquired in this study, patients presenting with a female phenotype and SRNS and male patients presenting with genital abnormalities should especially be screened to take advantage of the important genetic information on potential Wilms' tumor risk and differential therapy. This will also help to provide more data on the phenotype/genotype correlation in this patient population.
Ruf
Rainer G
RG
Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Schultheiss
Michael
M
Lichtenberger
Anne
A
Karle
Stephanie M
SM
Zalewski
Isabella
I
Mucha
Bettina
B
Everding
Anne Schulze
AS
Neuhaus
Thomas
T
Patzer
Ludwig
L
Plank
Christian
C
Haas
Johannes P
JP
Ozaltin
Fatih
F
Imm
Anita
A
Fuchshuber
Arno
A
Bakkaloglu
Aysin
A
Hildebrandt
Friedhelm
F
D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004351:Drug Resistance; D005091:Exons; D005260:Female; D005838:Genotype; D018238:Gonadoblastoma / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D018309:Neoplasms, Gonadal Tissue / Q000453:epidemiology / Q000235:genetics; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D010641:Phenotype; D015995:Prevalence; D013256:Steroids / Q000627:therapeutic use; D014564:Urogenital Abnormalities / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics*
D013256:Steroids; D025721:WT1 Proteins