Kidney Week

Abstract: FR-PO0141

Relatively Common NPHS1 Variants Contribute to a Mild Steroid-Resistant Nephrotic Syndrome

Session Information

• Hereditary Glomerular and Tubulointerstitial Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Asakawa, Jota, Toranomon Byoin, Minato, Tokyo, Japan

Jota Asakawa, MD

• Wada, Takehiko, Toranomon Byoin, Minato, Tokyo, Japan

Takehiko Wada, MD, PhD

• Sekine, Akinari, Toranomon Byoin, Minato, Tokyo, Japan

Akinari Sekine, MD

• Hiramoto, Ryugo, Matsudo Shiritsu Sogo Iryo Center, Matsudo, Chiba Prefecture, Japan

Ryugo Hiramoto, MD

• Pham, Xuyen Thi, Kansai Ika Daigaku, Hirakata, Osaka Prefecture, Japan

Xuyen Thi Pham, MD

• Rahmawati, Nanda Yuli, Kansai Ika Daigaku, Hirakata, Osaka Prefecture, Japan

Nanda Yuli Rahmawati, PhD

• Nozu, Kandai, Kobe Daigaku, Kobe, Hyogo Prefecture, Japan

Kandai Nozu, MD, PhD

• Ubara, Yoshifumi, Toranomon Byoin, Minato, Tokyo, Japan

Yoshifumi Ubara, MD, PhD

• Tsukaguchi, Hiroyasu, Kansai Ika Daigaku, Hirakata, Osaka Prefecture, Japan

Hiroyasu Tsukaguchi, MD, PhD

Background

Disruption of the slit diaphragm complex comprises one of the fundamental mechanisms of nephrotic syndrome. Variants in NPHS1, encoding nephrin, a major component of the slit diaphragm, are responsible for a spectrum of nephrotic syndrome (NS) ranging from congenital NS (CNS) to adult steroid-resistant NS (SRNS). NPHS1 variants account for 40% of CNS, while the contribution of NPHS1 variants to adult SRNS remains poorly defined.

Methods

We analyzed the mutations in the SRNS genes by the targeted NGS and assessed the pathogenicity of the variants based upon the ACMG/AMP criteria, allele frequency in jMorp 38KJPN, and In silico prediction(REVEL score). Cellular trafficking of NPHS1 variants was examined in a transient transfection with COS-7 cells.

Results

We first studied a 52-year-old male with NS (case 1), whose onset of NS was at age 3 years(yr). Steroid-resistant proteinuria was consistently detected on annual urinalysis throughout adulthood. A kidney biopsy performed at the age of 51 yr revealed findings of FSGS, and his eGFR gradually declined from 60 to 20 mL/min/1.73m² over 10 years. Genetic analysis revealed the biallelic NPHS1 variants (p.V822M and p.R379W). Notably, p.V822M is a relatively common allele with an allele frequency of approximately 1/5,000 in a control of Japanese population. Further genetic survey revealed two other mild SRNS cases harbor biallelic NPHS1 variants with one p.V822M variant: p.C265R (case 2, sibs age 32 yr and 25 yr) and exon 22 deletion (case 3, age 25yr). Both cases developed NS since the early childhood and had continued mild to moderate SRNS with MCNS histology over adulthood. The proteinuria levels currently ranged from 0.5 to1.1 g/gCr with eGFR ranging from 94 to 116. Literature review showed the four other p.V822M cases (p.R460Q, p.V822M homozygosity, p.G1056Ffs*41, p.L719Pfs*4). Expression study with COS-7 cells revealed that p.V822M variants reach the cell surface, whereas the partnered rare variants are retained in the ER, consistent with a hypomorphic phenotype.

Conclusion

Our results indicate that p.V822M represent a common risk allele of SRNS with MCNS or FSGS histology. The defective SD likely confers a susceptibility to immunogenic stimuli and predisposes to a relapsing phenotype. NPHS1 genotyping should be considered in SRNS, which will help molecular diagnosis and treatment choice.

Acknowledgment

None