Kidney Week

Abstract: FR-PO688

Severe Kidney Dysplastic Phenotypes Caused by WT1 Exon 9 Missense Variants

Session Information

• Pediatric Nephrology - 1
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

• 1900 Pediatric Nephrology

Authors

• Tran Thuy, Huong Quynh, Kansai Medical University, Second Department of Internal Medicine, Hirakata, Osaka, Japan

Huong Quynh Tran Thuy, MD

• Nguyen, Tuyen Thi Thanh, Kansai Medical University, Department of Genome Editing, Hirakata, Osaka, Japan

Tuyen Thi Thanh Nguyen, DrMed

• Fukui, Kenji, Osaka Medical and Pharmaceutical University, Faculty of Medicine, Department of Biochemistry, Takatsuki, Osaka, Japan

Kenji Fukui

• Nagano, China, Kobe University Graduate School of Medicine, Department of Pediatrics, Kobe, Hyogo, Japan

China Nagano, MD, PhD

• Nozu, Kandai, Kobe University Graduate School of Medicine, Department of Pediatrics, Kobe, Hyogo, Japan

Kandai Nozu, MD, PhD

• Hamada, Riku, Tokyo Metropolitan Childrens Medical Center, Department of Nephrology, Fuchu, Tokyo, Japan

Riku Hamada, MD

• Tsukaguchi, Hiroyasu, Kansai Medical University, Second Department of Internal Medicine, Hirakata, Osaka, Japan

Hiroyasu Tsukaguchi, MD, PhD

Introduction

Mutations of the Wilms tumor suppressor-1 gene (WT1) are typically linked to a triad of glomerulopathy, defective genital development, and Wilms' tumor. The hallmark clinical phenotype Denys-Drash Syndrome (DDS, OMIM194080) is caused by Exon 9 missense variants. p.Arg467Trp is the most commonly reported and accounts for approximately 50% of DDS.

Case Description

We recently found the WT1 p.Arg467Gln variants in five neonates with early onset ESRD (3 males, 2 females). Most cases developed ESRD within the first month of their life (median 8 days, range one day to 90 days). Three of them underwent bilateral nephrectomy remain healthy after kidney transplantation. Two (cases 1 and 2) show hyperechoic, normal or smaller kidneys on ultrasonography. Renal histology (case 3) revealed severe mesangial sclerosis with tubular dysgenesis and some overgrowth of stromal elements. Two males showed external genital abnormality (cryptorchidism, hypospadias, etc). One child (case 2) had lung hypoplasia (Potter syndrome). All were sporadic with the exception of case 1 affecting the two siblings.
The pathogenic p.Arg467Gln variant, which substitutes the most frequent, hot-spot Arg467 residue in the 3^rd zinc finger and typically causes Denys-Drash syndrome. Structural modeling predicted that an Arg-to-Trp substitution confers obvious structural hinderance for the 3^rd Zinc finger to bind the DNA, consistent with the inability to transactivate the luciferase functional assay. On the other hand, an Arg-to-Gln substitution modestly altered the hydrogen bonding for the DNA binding. Reviews of previous clinical reports showed that p.Arg467Gln leads to earlier onset NS and faster progression to ESRD compared to the p.Arg467Trp (p.Arg467Gln n=6, onset 0.04±0.02 year, ESRD 0.17±0.07 year, vs p.Arg467Trp n=40, onset 1.4±0.2 year, ESRD 2.29±0.4 year).

Discussion

We found that WT1 p.Arg467Gln tend to cause severe kidney dysplastic phenotype compared to the classic DDS variant p.Arg467Trp. Further study is necessary to see whether p.Arg467Gln have functionally more deteriorating effects on transcription predisposing to severe nephron dysplasia than does p.Arg467Trp or other second genetic factors contribute to modify the severe nephron developmental defects.