Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome
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 pathog...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
The Korean Society of Nephrology
2020-12-01
|
| Series: | Kidney Research and Clinical Practice |
| Subjects: | |
| Online Access: | https://doi.org/10.23876/j.krcp.20.111 |
| _version_ | 1818417408681967616 |
|---|---|
| author | Kandai Nozu Yutaka Takaoka Hirofumi Kai Minoru Takasato Kensuke Yabuuchi Tomohiko Yamamura Tomoko Horinouchi Nana Sakakibara Takeshi Ninchoji China Nagano Kazumoto Iijima |
| author_facet | Kandai Nozu Yutaka Takaoka Hirofumi Kai Minoru Takasato Kensuke Yabuuchi Tomohiko Yamamura Tomoko Horinouchi Nana Sakakibara Takeshi Ninchoji China Nagano Kazumoto Iijima |
| author_sort | Kandai Nozu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T12:06:19Z |
| format | Article |
| id | doaj.art-f60200c630c549e6ac5bfb2c447749e4 |
| institution | Directory Open Access Journal |
| issn | 2211-9132 |
| language | English |
| last_indexed | 2024-12-14T12:06:19Z |
| publishDate | 2020-12-01 |
| publisher | The Korean Society of Nephrology |
| record_format | Article |
| series | Kidney Research and Clinical Practice |
| spelling | doaj.art-f60200c630c549e6ac5bfb2c447749e42022-12-21T23:01:53ZengThe Korean Society of NephrologyKidney Research and Clinical Practice2211-91322020-12-0139440241310.23876/j.krcp.20.111j.krcp.20.111Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndromeKandai Nozu0Yutaka Takaoka1Hirofumi Kai2Minoru Takasato3Kensuke Yabuuchi4Tomohiko Yamamura5Tomoko Horinouchi6Nana Sakakibara7Takeshi Ninchoji8China Nagano9Kazumoto Iijima10Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDivision of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, JapanDepartment of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, JapanLaboratory for Human Organogenesis, RIKEN Center for Biosystems Dynamics Research, Kobe, JapanLaboratory for Human Organogenesis, RIKEN Center for Biosystems Dynamics Research, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanAlport 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.https://doi.org/10.23876/j.krcp.20.111alport syndromeglomerular basement membraneinduced pluripotent stemsplicing |
| spellingShingle | Kandai Nozu Yutaka Takaoka Hirofumi Kai Minoru Takasato Kensuke Yabuuchi Tomohiko Yamamura Tomoko Horinouchi Nana Sakakibara Takeshi Ninchoji China Nagano Kazumoto Iijima Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome Kidney Research and Clinical Practice alport syndrome glomerular basement membrane induced pluripotent stem splicing |
| title | Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome |
| title_full | Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome |
| title_fullStr | Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome |
| title_full_unstemmed | Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome |
| title_short | Genetic background, recent advances in molecular biology, and development of novel therapy in Alport syndrome |
| title_sort | genetic background recent advances in molecular biology and development of novel therapy in alport syndrome |
| topic | alport syndrome glomerular basement membrane induced pluripotent stem splicing |
| url | https://doi.org/10.23876/j.krcp.20.111 |
| work_keys_str_mv | AT kandainozu geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT yutakatakaoka geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT hirofumikai geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT minorutakasato geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT kensukeyabuuchi geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT tomohikoyamamura geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT tomokohorinouchi geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT nanasakakibara geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT takeshininchoji geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT chinanagano geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome AT kazumotoiijima geneticbackgroundrecentadvancesinmolecularbiologyanddevelopmentofnoveltherapyinalportsyndrome |