Kidney Res Clin Pract.
2020 Dec;39(4):402-413. 10.23876/j.krcp.20.111.
Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome
- Nozu K
1 - Takaoka Y2
- Kai H3
- Takasato M4,5
- Yabuuchi K4
- Yamamura T1
- Horinouchi T1
- Sakakibara N1
- Ninchoji T1
- Nagano C1
- Iijima K1
- Affiliations
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- 1Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- 2Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, Japan
- 3Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- 4Laboratory for Human Organogenesis, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
- 5Laboratory of Molecular Cell Biology and Development, Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- KMID: 2509802
- DOI: http://doi.org/10.23876/j.krcp.20.111
Abstract
- Alport syndrome (AS) is a progressive inherited kidney disease characterized by hearing loss and ocular abnormalities. There are three forms of AS depending on inheritance mode: X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, which encodes type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode type IV collagen α3 or α4 chain, respectively. In male XLAS or ARAS cases, end-stage kidney disease (ESKD) develops around a median age of 20 to 30 years old, while female XLAS or ADAS cases develop ESKD around a median age of 60 to 70 years old. The diagnosis of AS is dependent on either genetic or pathological findings. However, determining the pathogenicity of the variants detected by gene tests can be difficult. Recently, we applied the following molecular investigation tools to determine pathogenicity: 1) in silico and in vitro trimer formation assay of α345 chains to assess triple helix formation ability, 2) kidney organoids constructed from patients’ induced pluripotent stem cells to identify α5 chain expression on the glomerular basement membrane, and 3) in vitro splicing assay to detect aberrant splicing to determine the pathogenicity of variants. In this review article, we discuss the genetic background and novel assays for determining the pathogenicity of variants. We also discuss the current treatment approaches and introduce exon skipping therapy as one potential treatment option.
