Abstract: PO1604
NPHS1 Variants Can Cause Persistent Asymptomatic Proteinuria: Genetic and Clinical Characteristics of Patients with NPHS1 Variants in Japan
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - 1
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Yamamura, Tomohiko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Horinouchi, Tomoko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Ishiko, Shinya, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Aoto, Yuya, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Sakakibara, Nana, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Nagano, China, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Ninchoji, Takeshi, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Shima, Yuko, Department of Pediatrics, Wakayama Medical University, Wakayama, Japan
- Nakanishi, Koichi, Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
- Nozu, Kandai, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Iijima, Kazumoto, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
Background
NPHS1 gene, which encodes nephrin, is known as a causative gene of congenital nephrotic syndrome (CNS). In addition, recently, it had been recognized that NPHS1 variants present with childhood steroid resistant nephrotic syndrome (SRNS) or focal segmental glomerular sclerosis (FSGS). However, it is not well known that this gene variants account for more milder phenotypes such as asymptomatic proteinuria.
Methods
347 unrelated patients with CNS, infantile nephrotic syndrome, FSGS and asymptomatic proteinuria were screened for podocyte related genes including NPHS1 by using targeted exome sequencing. A retrospective review of clinical information was conducted for the cases with pathogenic variants in NPHS1.
Results
We identified 15 NPHS1 autosomal recessive pathogenic variants in 15 cases including 2 siblings. Regarding clinical manifestation, 6 cases showed CNS, 5 cases showed SRNS and 4 cases showed only asymptomatic mild to moderate proteinuria. The median age developing proteinuria in cases with SRNS and asymptomatic proteinuria was 6 years old. Pathological evaluation for 12 cases revealed that 11 cases showed minor glomerular abnormality and 1 case showed findings resemble membranous nephropathy. Genetic analysis revealed the variants c.2464G>A p.(V822M) and c.2515del were variantal hot spots in the Japanese population and all 6 cases having V822M showed milder phonotypes such as SRNS (n=2) or asymptomatic proteinuria (n=4) and no one showed CNS.
Conclusion
In this study, NPHS1 variants were detected not only in cases with CNS and SRNS, but also in cases with asymptomatic proteinuria. Shono et al. have previously reported that V822M was a causative variant in cases with familial nephrotic syndrome who showed complete remission and functional analysis revealed that this variant leads to milder phenotype through mechanisms of (1)mild reduction of cell surface expression, (2)motion and trafficking restriction on surface and (3)interfering with assembly of microdomain on surface (Hum Mol Genet. 2009). Our study confirmed this variant leads to very mild phenotypes of SRNS or even the asymptomatic proteinuria and broadened the understanding of clinical manifestations of cases with NPHS1 variants.