Clarification of pathophysiology and development of new treatment for lowe syndrome using patient-derived proximal tubular cells

• Project/Area Number: 17K16087
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Kobe University
• Principal Investigator: Minamikawa Shogo 神戸大学, 医学研究科, 医学研究員 (10772634)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: Lowe syndrome / Dent disease 2 / urine-derived cell / OCRL activity / Lowe症候群 / 尿中落下細胞 / 次世代シークエンサー / ナンセンスリードスルー / Dent病 / OCRL

Outline of Final Research Achievements

We collected cases of patients with Dent disease 2 (D2) and Lowe syndrome (LS), and genetically diagnosed 14 cases of D2 and 14 cases of LS by a next-generation sequencer. We revealed the differences in phenotype and genotype between D2 and LS. Because we could not confirm the difference in the expression of OCRL in the urine-derived cell lines derived from patients with D2 and LS, we created an OCRL overexpressing cell line into which a vector containing the OCRL mutation was introduced. As a result, in the LS cell line, OCRL expression and activity were significantly decreased compared with D2. On the other hand, the nonsense readthrough was introduced into the LS cell line having the nonsense mutation, but no improvement in OCRL expression was observed.

Academic Significance and Societal Importance of the Research Achievements

同一遺伝子の変異が原因であるにも関わらず全く異なる表現型を示すDent病2型（D2）とLowe症候群（LS）の病態の違いについては未だ不明な点が多く、有効な治療法もみつかっていない。我々はこれらの疾患に対して、遺伝子型と表現型、さらにはOCRL発現量やOCRL活性を比較することで病態解明を試み、さらにはLSの治療法としてナンセンスリードスルー療法の有用性について検討した。残念ながら治療法確立とまでは進んでいないが、病態解明に向けて引き続き研究を継続していく予定である。

Research Products

• [Journal Article] Molecular mechanisms determining severity in patients with Pierson syndrome (2020)
  • Author(s): Minamikawa Shogo、Miwa Saori、Inagaki Tetsuji、Nishiyama Kei、Kaito Hiroshi、Ninchoji Takeshi、Yamamura Tomohiko、Nagano China、Sakakibara Nana、Ishimori Shingo、Hara Shigeo、Yoshikawa Norishige、Hirano Daishi、Harada Ryoko、Hamada Riku、Matsunoshita Natsuki、Nagata Michio、Shima Yuko、Nozu Kandai
  • Journal Title: Journal of Human Genetics Volume: 65 Issue: 4 Pages: 355-362
  • DOI: 10.1038/s10038-019-0715-0
  • NAID: 120006811107
  • Peer Reviewed
• [Presentation] Lowe症候群とDent disease-2の2疾患における分子生物学的発症機序の解明 (2020)
  • Author(s): 榊原 菜々、南川 将吾、野津 寛大、飯島 一誠
  • Organizer: 第55回日本小児腎臓病学会学術集会
• [Presentation] Clinical and genetic characteristics in Dent disease 2 and Lowe syndrome. (2019)
  • Author(s): 榊原 菜々、南川 将吾、野津 寛大、飯島 一誠
  • Organizer: ASN Kidney Week 2019
  • Int'l Joint Research
• [Presentation] Comparison of clinical and genetic characteristics between Dent disease-1 and Dent disease-2 (2019)
  • Author(s): 榊原 菜々、南川 将吾、野津 寛大、飯島 一誠
  • Organizer: IPNA Congress 2019
  • Int'l Joint Research