Understanding the pathogenesis mechanism of Lowe syndrome and Dent disease-2 and new therapeutic development

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15864
• 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: Kobe University
• Principal Investigator: Nana Sakakibara 神戸大学, 医学研究科, 特務講師 (90814319)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: OCRL / Lowe症候群 / Dent disease-2

Outline of Final Research Achievements

Both Lowe syndrome and Dent disease-2 are caused by OCRL mutations, but their clinical severities differ substantially; further, their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1-7 and 8-24 cause Dent disease-2 and Lowe syndrome, respectively; thus, OCRL isoforms are responsible for differences in disease severity. We successfully cloned novel OCRL isoform transcripts for exons 6-24 and identified the translation-initiation codons in exon 8.
The isoforms translated from this novel transcript showed the same enzymatic activity as wild-type OCRL, consistent with the phenotypic divergence between OCRL exon 1-7 and exon 8-24. Our results will accelerate the elucidation of disease conditions associated with OCRL-related abnormalities, as well as promote the development of novel therapeutic agents for such conditions.

Free Research Field

小児腎臓病学

Academic Significance and Societal Importance of the Research Achievements

Dent disease-2がLowe症候群に比べ明らかに軽症な表現型を示す理由は、これまで明らかにされていなかったが、本研究ではDent disease-2患者にのみ発現するisoformのクローニングに成功し、またこのisoformがOCRL蛋白としての機能を持つことを証明した。
本研究は長らく不明であったLowe症候群およびDent disease-2の発症メカニズムを解明するだけでなく、こLowe症候群の遺伝子治療の開発への足がかりとなる非常に重要な研究と考えている。