Abstract: FR-PO441
Alport Syndrome Caused by a Novel Intronic Mutation Leading to Partial Aberrant mRNA Splicing: A Case Report
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
- Rao, Dipti, Radboudumc, Nijmegen, Gelderland, Netherlands
- van Geel, Michel, Maastricht Universitair Medisch Centrum+, Maastricht, Limburg, Netherlands
- van den Berge, Bartholomeus Tideman, Radboudumc, Nijmegen, Gelderland, Netherlands
- Jansen, Jitske, Radboudumc, Nijmegen, Gelderland, Netherlands
- Smeets, Bart, Radboudumc, Nijmegen, Gelderland, Netherlands
- Wetzels, Jack F., Radboudumc, Nijmegen, Gelderland, Netherlands
- Maas, Rutger J., Radboudumc, Nijmegen, Gelderland, Netherlands
Introduction
Alport syndrome (AS) is a hereditary disorder of type IV collagen. X-linked Alport syndrome (XLAS), caused by a mutation in the COL4A5 gene, accounts for over 80% of all cases. Hematuria is the main initial symptom of AS. Most male patients develop end-stage-kidney-disease (ESKD) at young age, though there is variability in rate of progression. Genetic testing covering the coding regions of all three COL4A3, COL4A4 and COL4A5 genes is recommended in patients with suspected AS. However, in 10-20% of patients a mutation cannot be detected.
Case Description
We report a 63-year-old male who developed hematuria by one year of age. Over the years he developed proteinuria. The estimated glomerular filtration rate (eGFR) declined gradually; he reached ESKD at the age of 60.
Kidney biopsy during childhood showed tubulointerstitial abnormalities and a thin GBM with segmental splitting. A skin biopsy showed absence of α5(IV) chains in the epidermal basement membrane, thus providing histological proof for diagnosis of XLAS.
Glomerular hematuria was also detected in the patients’ mother and both daughters; none of them developed proteinuria nor reduced eGFR.
Initial genetic analysis by next-generation sequencing of the Alport gene panel (COL4A3-COL4A4-COL4A5) failed to detect the genetic cause. Reverse-transcriptase-PCR analysis on RNA extracted from urine-derived podocyte-lineage cells detected partial cryptic splicing, retaining an extra sequence between exon 21 and 22 derived from intron 21 (r.1423_1424ins1423+1187_1423+1230), putatively resulting in a frameshift and premature stop upon translation (p.(Asp476Profs*96)). Subsequent Sanger sequencing revealed a hemizygous deep intronic variant c.1423+1175G>T in the COL4A5 gene.
Discussion
We report a case of XLAS caused by a novel deep intronic mutation in COL4A5. Pathogenicity was experimentally confirmed by analysis of RNA isolated from urine-derived podocyte-lineage cells, which offers a non-invasive diagnostic method.
The specific mutation strikingly results in partial aberrant mRNA splicing, putatively resulting in co-existence of a shorter, non-functional COL4A5 protein and a normal functional protein.
This finding could explain the relatively mild phenotype with development of ESKD at an older age as is common for XLAS.