Transcriptomic analysis reveals a critical role for activating G_sα mutations in spontaneous feline hyperthyroidism

Area of Science:

• Veterinary Medicine
• Molecular Biology
• Endocrinology

Background:

• Feline hyperthyroidism (FHT) is a common endocrine disorder in older cats, characterized by elevated thyroid hormones without thyroid-stimulating hormone (TSH).
• The molecular mechanisms underlying FHT are not fully understood, but it shares similarities with human toxic multinodular goiter, linked to mutations in the TSH receptor (TSHR) and Gsα genes.

Purpose of the Study:

• To investigate the molecular pathogenesis of FHT by analyzing gene expression and identifying genetic variations in feline thyroid tissue.
• To determine the role of TSHR and Gsα mutations in the development of TSH-independent hyperthyroidism in cats.

Main Methods:

• RNA-sequencing (RNA-seq) transcriptomic analysis of thyroid tissue from hyperthyroid and euthyroid cats.
• Detection and characterization of missense variants in TSHR and Gsα genes using RNA-seq data.
• In vitro assessment of the functional impact of identified Gsα mutations on cAMP production.

Main Results:

• Differentially expressed genes and dysregulated pathways downstream of TSHR were identified in FHT.
• Acquired missense variants in TSHR and Gsα were detected in feline thyroid tissue, but not in germline DNA.
• All advanced FHT cases exhibited at least one missense variant in Gsα, which demonstrably increased cAMP production in vitro, indicating constitutive activation.

Conclusions:

• Constitutive activation of TSHR signaling, primarily through acquired Gsα mutations, is central to TSH-independent thyroid hormone overproduction in FHT.
• These findings identify a novel therapeutic target pathway for managing feline hyperthyroidism.