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Mutations in NPHS₂ Encoding Podocin Are a Prevalent Cause of Steroid-Resistant Nephrotic Syndrome among Israeli-Arab Children

Yaacov Frishberg^*, Choni Rinat^*, Orli Megged^*, Eli Shapira^*, Sofia Feinstein^* and Annick Raas-Rothschild

*Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel; and Department of Human Genetics, Hadassah University Medical Center and Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.

Correspondence to Dr. Yaacov Frishberg, Division of Pediatric Nephrology, Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031, Israel. Phone: 972-2-6666144; Fax: 972-2-6555689; E-mail: yaacov{at}md.huji.ac.il

ABSTRACT. Steroid-resistant nephrotic syndrome (SRNS) represents a heterogeneous group of kidney disorders that are often resistant to other immunosuppressive agents and tend to progress to end-stage renal failure. Mutations in the gene NPHS2 that encode a protein named podocin have recently been found in a recessive form of SRNS. Ten children from two inbred families of Israeli-Arab descent presented with SRNS. Renal histologic findings were of diffuse mesangial proliferation. Six patients reached end-stage renal failure, but nephrotic syndrome did not recur after renal transplantation. Mutation analysis of NPHS2 revealed that they were homozygous for the C412T mutation (R138X). Eighteen children were subsequently analyzed with SRNS due to biopsy-proven focal segmental glomerulosclerosis (FSGS) from unrelated families of Israeli-Arab descent. Analysis disclosed six additional patients (33%) bearing the same mutation in a homozygous pattern. Three of them had no affected relatives, although they came from large families. Taken together, of the 27 patients tested (familial and nonfamilial), 15 patients (55%) were homozygous for the mutation (R138X). They all shared the same haplotype and were homozygous for the A1023G polymorphism, thus pointing to a possible founder effect. Thirteen children of Israeli-Jewish origin with SRNS and biopsy-proven FSGS and 15 children of both ethnic groups with steroid-responsive FSGS were tested, and none was found to have mutations in NPHS2. The results of this study demonstrate that mutations in NPHS2 are a common cause of SRNS in Israeli-Arab children. Mutations in NPHS2 may cause SRNS in nonfamilial cases. The interethnic differences in the occurrence of NPHS2 mutations may explain, in part, the previous observation that Arab patients with FSGS in Israel have a worse prognosis as compared with Jewish patients, despite similar presenting symptoms and medical management. Identifying the causing mutation will enable clinicians to avoid unnecessary immunosuppressive therapeutic trials in newly diagnosed patients and to provide prenatal diagnosis to families at risk.

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