Elucidating factors underlying the diverse phenotypes observed in SLC26A4 gene mutations

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K09728
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Ito Taku 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (40401400)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: SLC26A4 / 前庭水管拡大 / ペンドレッド / メラニン / マクロファージ / Mondini / IP-II

Outline of Final Research Achievements

Research using knockout mice was conducted to elucidate the pathogenic mechanisms caused by SLC26A4 gene mutations. Morphological analyses showed distinct labeling patterns of macrophage markers between wildtype and mutant mice. Three-dimensional analysis further unveiled a distinct polarity in the morphology of activated macrophages.Reanalysis of microarray data identified upregulated molecules in the stria vascularis of mutants. Comprehensive analysis integrating single-cell data elucidated changes in macrophages. These results suggest SLC26A4 deficiency affects macrophage activation and polarity formation, leading to degeneration of the spiral ligament and stria vascularis.
Experiments administering the mTOR inhibitor sirolimus were planned but suspended due to revised animal facility regulations. While this research uncovered part of the mechanism underlying the diverse phenotypes associated with SLC26A4 mutations, further analysis, including the sirolimus experiments, is necessary.

Free Research Field

耳鼻咽喉科学

Academic Significance and Societal Importance of the Research Achievements

本研究は、SLC26A4遺伝子変異による難聴・平衡障害の発症メカニズムの一端を明らかにした点で学術的に意義がある。SLC26A4欠損がマクロファージの機能異常を引き起こし、内耳の変性に関与することを示した。この知見は内リンパ水腫などの内耳奇形の分子病態解明に貢献する。
一方、社会的には難聴患者の病因解明と新規治療法開発への手がかりを与えた。SLC26A4遺伝子変異は先天性難聴の主要な原因であり、マクロファージ制御を標的とした新しいアプローチが有望視される。さらに、m-TOR阻害剤によるマクロファージ活性調節が内耳変性抑制に有効かを検証する重要性が示された。