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Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome

Kidney Research and Clinical Practice 2020년 39권 4호 p.402 ~ 413
Nozu Kandai, Takaoka Yutaka, Kai Hirofumi, Takasato Minoru, Yabuuchi Kensuke, Yamamura Tomohiko, Horinouchi Tomoko, Sakakibara Nana, Ninchoji Takeshi, Nagano China, Iijima Kazumoto,
소속 상세정보
 ( Nozu Kandai ) - Kobe University Graduate School of Medicine Department of Pediatrics
 ( Takaoka Yutaka ) - Kobe University Hospital Division of Medical Informatics and Bioinformatics
 ( Kai Hirofumi ) - Kumamoto University Graduate School of Pharmaceutical Sciences Department of Molecular Medicine
 ( Takasato Minoru ) - RIKEN Center for Biosystems Dynamics Research Laboratory for Human Organogenesis
 ( Yabuuchi Kensuke ) - RIKEN Center for Biosystems Dynamics Research Laboratory for Human Organogenesis
 ( Yamamura Tomohiko ) - Kobe University Graduate School of Medicine Department of Pediatrics
 ( Horinouchi Tomoko ) - Kobe University Graduate School of Medicine Department of Pediatrics
 ( Sakakibara Nana ) - Kobe University Graduate School of Medicine Department of Pediatrics
 ( Ninchoji Takeshi ) - Kobe University Graduate School of Medicine Department of Pediatrics
 ( Nagano China ) - Kobe University Graduate School of Medicine Department of Pediatrics
 ( Iijima Kazumoto ) - Kobe University Graduate School of Medicine Department of Pediatrics

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.

키워드

Alport syndrome; Glomerular basement membrane; Induced pluripotent stem; Splicing

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