Generation and characterization of a hypothyroidism rat model with truncated thyroid stimulating hormone receptor

Area of Science:

• Endocrinology
• Genetics
• Developmental Biology

Background:

• Thyroid stimulating hormone receptor (TSHR) is crucial for thyroid function and development.
• Mutations in TSHR are linked to congenital hypothyroidism (CH) in humans, but lack animal models for functional study.

Purpose of the Study:

• To create and characterize a novel rat model of congenital hypothyroidism (CH) caused by TSHR mutations.
• To investigate the functional consequences of a truncated TSHR in vivo.
• To explore potential therapeutic interventions for CH.

Main Methods:

• CRISPR/Cas genome editing was used to generate a Tshr ^Df/Df rat model.
• Phenotypic analysis included assessment of growth, thyroid morphology, hormone levels, and fertility.
• Gene expression analysis of thyroid-specific genes (Tpo, Tg, Nis) was performed at mRNA and protein levels.

Main Results:

• The Tshr ^Df/Df rats exhibit phenotypes mirroring human TSHR Y444X CH patients, including dwarfism, thyroid aplasia, infertility, and resistance to TSH.
• Serum thyroid hormone levels were significantly reduced.
• Thyroid development was severely impaired due to suppressed expression of Tpo, Tg, and Nis.
• Phenotypic manifestations were partially reversible with levothyroxine (L-T4) treatment.

Conclusions:

• The Tshr ^Df/Df rat is a valuable new genetic model for studying congenital hypothyroidism (CH).
• This model elucidates the role of TSHR in thyroid development and identifies downstream effects on thyroid-specific gene expression.
• It provides a platform for understanding thyroid hormone-sensitive organ development and testing CH therapies.