Abstract: FR-PO447
Investigation of the Pathogenicity of Novel Missense Variants in the ARHGAP24 Gene by Quantitative Analysis of the Active Rac1: Two Cases of Proteinuria With Renal Dysfunction
Session Information
- Pediatric Nephrology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1102 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Kondo, Atsushi, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Nagano, China, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Kitakado, Hideaki, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Masuda, Chika, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Ishiko, Shinya, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Aoto, Yuya, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Sakakibara, Nana, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Horinouchi, Tomoko, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Yamamura, Tomohiko, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Iijima, Kazumoto, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo, Japan
- Nozu, Kandai, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
Introduction
Proteinuric kidney diseases including steroid-resistant nephrotic syndrome (SRNS) can lead to renal dysfunction, and one of its causative genes is ARHGAP24 (NM_001025616.2). It encodes a Rho-GTPase activating protein and acts as a negative regulator for Rac1. Excessive activation of Rac1 in podocytes has been reported to cause foot process effacement, and lead to persistent proteinuria and SRNS.
Case Description
Case 1: The patient is a 15-year-old female. She developed SRNS at the age of five. Although some immunosuppressive therapy had been administrated, it was ineffective. At the age of ten, a renal biopsy was performed and the pathological diagnosis was focal segmental glomerulosclerosis. Subsequently, her renal function gradually declined to CKD Stage2. We performed a comprehensive genetic analysis of podocyte-related genes by targeted next-generation sequencing (NGS) using peripheral blood samples. A novel missense variant (c.1217G>T, p.(Ser406Ile)) in the ARHGAP24 gene was detected, and it was a de novo variant.
Case 2: The patient is a 26-year-old female. She has shown mild proteinuria from the age of ten. In adulthood, the proteinuria became more severe with renal dysfunction as CKD Stage2, so a detailed examination was performed. The pathological findings of the renal biopsy were minor glomerular abnormality. As in case 1, comprehensive genetic testing by targeted NGS was performed, and that revealed a novel missense variant (c.2234T>C, p.(Ile745Thr)) in the ARHGAP24.
For these two variants, the quantitative analysis of active Rac1 in HEK293T cells transfected with the ARHGAP24 plasmid vector carrying the variants was performed. As a result, both variants significantly increased active Rac1 compared to the wild type. Therefore, we concluded these novel missense variants are Pathogenic.
Discussion
It is definitely important to determine whether novel variants are pathogenic or not because almost immunosuppressive therapy for SRNS associated with genetic variants is often ineffective. In patients with ARHGAP24 variants, quantitative analysis of active Rac1 protein is a simple and universal test for its pathogenicity, and is useful in determining pathogenicity.