Transcriptomic analysis reveals a critical role for activating G s α mutations in spontaneous feline hyperthyroidism.

Autor: Hiron TK; Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, AL9 7TA, UK.; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK., Aguiar J; Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, AL9 7TA, UK.; Dick White Referrals, Station Farm, London Road, Six Mile Bottom, Cambridgeshire, CB8 0UH, UK., Williams JM; Department of Pathobiology and Population Sciences, The Royal Veterinary College, Hertfordshire, AL9 7TA, UK., Falcone S; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK., Norman PA; Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, AL9 7TA, UK., Elliott J; Department of Comparative Biomedical Science, The Royal Veterinary College, London, NW1 0TU, UK., Fowkes RC; Department of Comparative Biomedical Science, The Royal Veterinary College, London, NW1 0TU, UK.; Department of Small Animal Clinical Sciences, Michigan State University College of Veterinary Medicine, East Lansing, MI, 48824, USA., Syme HM; Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, AL9 7TA, UK., Davison LJ; Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire, AL9 7TA, UK. ldavison@rvc.ac.uk.; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK. ldavison@rvc.ac.uk.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Nov 20; Vol. 14 (1), pp. 28749. Date of Electronic Publication: 2024 Nov 20.
DOI: 10.1038/s41598-024-79564-z
Abstrakt: Feline hyperthyroidism (FHT) is a debilitating disease affecting > 10% of elderly cats. It is generally characterised by chronic elevation of thyroid hormone in the absence of circulating TSH. Understanding of the molecular pathogenesis of FHT is currently limited. However, FHT shares clinical and histopathological similarities with human toxic multinodular goitre, which has been associated with activating mutations in TSH receptor (TSHR) and G s α encoding genes. Using RNA-seq transcriptomic analysis of thyroid tissue from hyperthyroid and euthyroid cats, we identified differentially expressed genes and dysregulated pathways in FHT, many of which are downstream of TSHR. In addition, we detected missense variants in thyroid RNA-seq reads that alter the structure of both TSHR and G s α. All FHT-associated mutations were absent in germline sequence from paired blood samples. Only a small number of hyperthyroid cats demonstrated TSHR variation, however all thyroids from advanced cases of FHT carried at least one missense variant affecting G s α. The activating nature of the acquired G s α mutations was demonstrated by increased cAMP production in vitro. These data indicate that constitutive activation of signalling downstream of TSHR is central to the TSH-independent production of thyroid hormone in FHT, offering a novel therapeutic target pathway in this common disease.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: