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Recessive NPHS2 (Podocin) Mutations Are Rare in Adult-Onset Idiopathic Focal Segmental Glomerulosclerosis

Ning He^*, Alireza Zahirieh^*, Yan Mei^*, Brian Lee^*, Sean Senthilnathan^*, Betty Wong, Bettina Mucha, Friedhelm Hildebrandt, David E. Cole, Daniel Cattran^*, and York Pei^*

^* Division of Nephrology, Toronto General Hospital, University Health Network and University of Toronto, and Department of Laboratory Medicine and Pathobiology, Sunnybrook and Women’s College Health Science Centre and University of Toronto, Toronto, Ontario, Canada; and Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, Michigan

Address correspondence to: Dr. York Pei, Division of Nephrology, University Health Network, 8N838, 585 University Avenue, Toronto, Ontario, Canada M5G 2C4. Phone: 416-340-4257; Fax: 416-340-4999; E-mail: york.pei{at}uhn.on.ca

Recessive NPHS2 (podocin) mutations account for up to approximately 30% of steroid-resistant idiopathic FSGS in children and are associated with a reduced risk for disease recurrence after renal transplantation. R229Q, a missense variant that is present in 3.6% of the white population, has been implicated as a common disease-causing mutation. Given these clinical implications, we examined the role of NPHS2 mutations in a cohort of patients with adult-onset FSGS. We used denaturing HPLC to screen for heterozygous and homozygous gene variants in PCR-amplified DNA fragments that contained all exons and splice junctions of NPHS2. Bidirectional sequencing was performed to define all of the gene variants detected. With the use of the denaturing HPLC in a single-blind pilot study, 40 of 43 known NPHS2 mutations were detected from 22 pediatric patients with FSGS to establish a test sensitivity of 93%. This screen then was applied to 87 adult patients with idiopathic FSGS (15 steroid-sensitive, 63 steroid-resistant, and nine familial cases). In this latter cohort, compound heterozygous mutations were detected only in one patient with steroid-sensitive FSGS (R229Q and Q285fsX302) and no homozygous mutations. Overall, R229Q accounted for eight (80%) of ten of the putative mutant alleles that were detected in the study cohort. Contrary to the pediatric experience, recessive NPHS2 mutations are rare in this study population, suggesting that the pathogenesis of FSGS in adults may differ from that in children. These data do not support R229Q as a disease-causing mutation for steroid-resistant FSGS.

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