Functional elucidation of PNPAL4, a causative gene for mitochondrial respiratory chain abnormalities associated with sudden infant death

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15662
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Niigata University
• Principal Investigator: Nyuzuki Hiromi 新潟大学, 医歯学総合病院, 医員 (80793926)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: PNPLA4 / ミトコンドリア呼吸鎖異常症 / 乳児突然死 / ゼブラフィッシュ

Outline of Final Research Achievements

The purpose of this study was to clarify the molecular biological functions of PNPLA4, the gene responsible for mitochondrial respiratory chain disorders associated with sudden infant death. First, we generated PNPLA4 knockout zebrafish using the CRISPR/Cas9 system. Then, we confirmed the distribution of PNPLA4 mRNA expression by in situ hybridization and other methods. Furthermore, we performed comprehensive lipid analysis, protein expression analysis, and RNA-seq analysis of knockout zebrafish brain samples, and found significant changes in metabolites and gene expression related to lipid and energy metabolism. Through these studies, we have elucidated one aspect of the function of PNPLA4.

Free Research Field

小児医学

Academic Significance and Societal Importance of the Research Achievements

小児の進行性希少難病であるミトコンドリア呼吸鎖異常症の病態は未だ不明な点が多く、個々の原因遺伝子の詳細な機能を明らかにすることが病態解明の鍵となる。本研究を通じて、乳児突然死として発症したミトコンドリア呼吸鎖異常症の原因遺伝子の一つであるPNPLA4の機能の一側面が明らかとなった。今後のミトコンドリア呼吸鎖異常症の病態解明につながる大きな成果であり、将来的に新たな治療戦略の創出並びに乳児突然死の予防法提唱に寄与する可能性がある。