Identification of Genes Involved in the Severity of Alport Syndrome and Elucidation of the Mechanism of its Severity

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H04189
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kobe University
• Principal Investigator: Iijima Kazumoto 神戸大学, 医学研究科, 教授 (00240854)
• Co-Investigator(Kenkyū-buntansha): 高岡 裕 神戸大学, 医学部附属病院, 准教授 (20332281) ; 野津 寛大 神戸大学, 医学研究科, 特命教授 (70362796)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: アルポート症候群 / 重症化機序 / エクソンスキッピング

Outline of Final Research Achievements

It was confirmed that there was no correlation in clinical feature and genotype in the X-linked Alport syndrome (XLAS) female patients. Furthermore, since no disease-modifying gene mutations were identified in most severely ill patients, the severity of female XLAS patients was considered to be multifactorial. Molecular simulation analysis of the α3,4,5 (IV) chain revealed that when the exon with the stop codon was skipped, the α3,4,5 (IV) chain with COL4A5 truncating mutations showed three-dimensional structure similar to that of the normal α3,4,5 (IV) chain. These results strongly suggest that the modification of the truncating mutation to the non-truncating mutation by exon skipping therapy may attenuate XLAS. We also found that the severity of patients with COL4A5 missense mutations was correlated to the ability of the α3,4,5 (IV) chain to form trimers.

Free Research Field

小児科学、腎臓学

Academic Significance and Societal Importance of the Research Achievements

我々は、今回の研究結果をもとに、XLASのエソンスキッピング療法の開発に着手しており、XLASモデルマウスを用いた治療研究で、エクソンスキッピング療法が非常に有効であることを世界で初めて明らかにしており（Nat Commun. in press）、近々に臨床試験を開始する予定である。