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Abstract: SA-PO358

X-Linked Alport Syndrome Caused by Synonymous Mutation, p.Pro786Pro Inducing Incomplete Aberrant Exon Skipping in COL4A5

Session Information

Category: Trainee Case Report

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Aoto, Yuya, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan
  • Nozu, Kandai, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan
  • Horinouchi, Tomoko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan
  • Sakakibara, Nana, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan
  • Nagano, China, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan
  • Yamamura, Tomohiko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan
  • Shima, Yuko, Wakayama Medical University, Wakayama City, Japan
  • Nakanishi, Koichi, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Japan
  • Iijima, Kazumoto, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan
Introduction

X-linked Alport syndrome (XLAS) - a progressive hereditary kidney disease caused by mutations in COL4A5 gene coding type IV collagen α5 chain (α5(IV)), with the median age of developing end-stage renal failure in male XLAS patients of 25 years, and 70 or 90% of the patients had reached ESRD before the age 30 and 40 years, respectively. Additionally, patients with truncating mutations tend to show severe phenotypes.

Case Description

Two male siblings with mild phenotypes whose mother had hematuria, now 43, and 34 years old; both had hematuria since childhood. Their proteinuria appeared at 33, and 20 years, respectively. The elder recently developed ESRD, and the younger is still CKD-stage III b. The younger’s kidney biopsy at 31 years of age, showed a thin glomerular basement membrane and normal α5(IV) expression. Gene analysis revealed both possessing only a novel hemizygous synonymous variant of c.2358A>G (p.Pro786Pro) in COL4A5 exon 29 among all 3 genes responsible for Alport syndrome. Further transcript analysis revealed this single base substitution caused aberrant splicing of exon 29 complete skipping which was shown both in peripheral lymphocytes and urinary sediments. Exon 29 is constituted by 151bp and the skipping of this exon leads to a frameshift mutation at the transcript level and supposed to be showing severe phenotypes. However, a small amount of normally spliced transcript was also detected in the transcript from urinary sediments which might be because of incomplete aberrant splicing by the variant.

Discussion

The synonymous mutation can cause aberrant splicing in COL4A5. However, relatively mild phenotypes were led by the presence of a small amount of normally spliced transcript along with aberrant splicing. By this normal transcript, α5(IV) expression was positive on glomerulus. In conclusion, synonymous mutations can have pathogenicity by causing aberrant splicing. Additionally, normal transcript production along with the aberrantly spliced transcript prevents the patients from presenting severe phenotype. Accurate genetic diagnosis would be required to elucidate the onset mechanism by synonymous variants or presentation of atypically milder phenotypes.