Proof of a novel gene underlying B lymphocyte deficiency using genome-edited mice

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08153
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tohoku University
• Principal Investigator: Kikuchi Atsuo 東北大学, 医学系研究科, 教授 (30447156)
• Co-Investigator(Kenkyū-buntansha): 石井 直人 東北大学, 医学系研究科, 教授 (60291267)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 胎盤 / Bリンパ球 / ゲノム編集マウス / 希少疾患

Outline of Final Research Achievements

In this study, we did not identify any patient with B lymphocyte deficiency and a variant in gene X, and could not genetically prove this gene as the causative gene. Analysis of hematopoietic cells, including B lymphocytes, from genome-edited mice carrying the same mutation as the patient did not reveal significant differences compared to wild-type mice, and the patient's phenotype was not replicated.
On the other hand, homozygous mice were found to be almost embryonic lethal. Gross analysis of the fetus and placenta in homozygous mice showed growth retardation, pale bodies, subcutaneous edema, and subcutaneous hemorrhage. Histological analysis revealed that changes in the placenta were observed at the earliest stages, suggesting that placental damage might be the cause of embryonic lethality. Contrary to our initial expectations, it was suggested that one of the functions of this gene, previously unknown, is to be a molecule necessary for the normal development of the placenta.

Free Research Field

希少疾患

Academic Significance and Societal Importance of the Research Achievements

本研究ではヒトBリンパ球欠損症の症状を再現する目的で作成した、候補遺伝子変異を有するマウスの解析を通じて、予想外にもこの機能不明であった本遺伝子の産物の機能の一つとして胎盤の正常発生に必要な役割を果たしている可能性を挙げることができた。本研究で作成したモデルマウスを用いた今後の研究によって、本分子の生理的機能および欠損時の病態メカニズムのさらなる解明につながることが期待される。