Elucidation of the aggravation mechanism and new treatment in Pierson syndrome

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17297
• 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: Sakakibara Nana 神戸大学, 医学部附属病院, 医員 (90814319)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: LAMB2 / Pierson症候群 / スプライシング異常

Outline of Final Research Achievements

Eight cases of LAMB2 abnormalities were diagnosed by a comprehensive diagnosis system for congenital nephrotic syndrome, infantile nephrotic syndrome and steroid-resistant nephrotic syndrome using a next-generation sequencing (NGS). In addition, six cases of LAMB2 abnormality were examined and reported. This paper explains the mechanism of the disease severity by splicing analysis, for example, a case in which the disease seemed to be a missense mutation but was severe because it was actually a truncating mutation associated with abnormal splicing, and a case in which the disease was suspected to be severe because it showed abnormal splicing but was mild because it produced both normal and abnormal splicing products. However, even though missense mutations in the LN domain, which is important for the function of the LAMB2 protein, do not cause splicing abnormalities, some cases show severe phenotypes, suggesting that mechanisms other than splicing abnormalities may also be involved.

Free Research Field

小児腎臓病学

Academic Significance and Societal Importance of the Research Achievements

希少疾患であるLAMB2異常による小児ネフローゼ症候群について、本邦の小児例の臨床遺伝学的特徴を明らかにした。LAMB2異常により発症するPierson症候群は眼病変、精神運動発達遅滞、先天性ネフローゼ症候群を特徴とし、生後早期に末期腎不全に至る重症疾患であるが、一方で眼病変を呈さず、精神運動発達は正常で、腎機能も比較的長期に保持されるような軽症例も存在することが知られていた。私たちのこれまでの研究で、こういった重症度の違いを規定する要素の一つとして、スプライシングが関連していることを示してきたが、今回の研究で、一部のLAMB2異常においても、スプライシングが重症度規定因子となることを示した。