Molecular, histological, and functional analysis of the transcription factor PAX8 mutant G56S with a distinctive clinical picture

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K16936
• 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: Keio University
• Principal Investigator: Abe Kiyomi 慶應義塾大学, 医学部(信濃町), 共同研究員 (30594973)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: PAX8 / 先天性甲状腺機能低下症 / 甲状腺形成異常 / 未熟濾胞 / 腺腫様甲状腺腫 / 遺伝子改変マウス / 転写因子

Outline of Final Research Achievements

The thyroid-specific transcription factor PAX8 is indispensable for thyroid folliculogenesis. We studied a four-generation family with a novel PAX8 G56S variant, presenting congenital hypothyroidism (CH) in children and adenomatous goiter in adults. We created Pax8 G56S transgenic mice to investigate this age-dependent phenotype using CRISPR-Cas9.
We compared homozygous G56S mice with wild-type (Wt) littermates at 2 weeks and 3 months. G56S mice were viable long-term, showing growth retardation at 2 weeks but recovery by 3 months. They exhibited persistent hypothyroidism at 2 weeks and 3 months. Histologically, 2-week-old G56S mice showed follicular dysplasia, while 3-month-old mice exhibited irregular follicles and Sanderson polsters, characteristic of human adenomatous goiter.
G56S mice successfully reproduced the hypothyroidism and time-dependent transition of thyroid phenotype seen in the human G56S family. This demonstrated that the G56S variant is the cause of this phenotype.

Free Research Field

小児内分泌

Academic Significance and Societal Importance of the Research Achievements

新規PAX8バリアントG56Sにより甲状腺機能低下を来すこと、さらに組織学的に甲状腺濾胞形成不全と腺腫様甲状腺腫様の変化を来すことをマウスモデルで明らかにすることができた。既報のPAX8ノックアウトマウスと比較し、本遺伝子改変マウスは長期生存可能で軽症である。そのため継時的かつ長期的な甲状腺形態・病理学的観察が可能であり、未熟濾胞の変遷と腺腫様甲状腺腫の形成との関連の検証を通じて、新たな知見を得られると考える。その知見は、PAX8変異陽性患者の治療管理面で有用となるだけでなく、未だ原因が分かっていない甲状腺形成異常および甲状腺腺腫発生の分子機序の解明を行う上でも重要な意義をなすと考える。