Functional Characterization of the C-terminal Cholinesterase-Like (ChEL) Domain of the Thyroid Hormone Precursor Protein

<p>Vertebrate life is unsustainable without thyroid hormones. The only known precursor for thyroid hormone synthesis is thyroglobulin (Tg), composed of upstream regions I-II-III and a C-terminal cholinesterase-like (ChEL) domain, which bears 47% similarity to acetylcholinesterase (AChE). Mutations in Tg cause congenital hypothyroidism, the most common congenital endocrinopathy affecting 1 in 2,000-4,000 newborns, with a varying degree of phenotypic manifestations. Tg protein, regulated by TSH, is secreted to the lumen of thyroid follicles, where thyroxine (T₄) is formed primarily at the N-terminus, and triiodothyronine (T₃) is formed primarily in the ChEL domain. Previous <em>in vitro</em> studies indicated that the isolated ChEL domain (following a signal peptide) is competent for dimerization, secretion, iodination, and T₃ generation, but little to no T₄ generation. However, the <em>in vivo</em> biological relevance of the Tg-ChEL domain (in the absence of the remaining Tg molecule) is entirely unknown. Furthermore, the functional effects of several Tg-ChEL mutations responsible for congenital hypothyroidism remain to be elucidated. This project has two main objectives. Objective 1 examines the thyroid histological characteristics of a genetically engineered mouse model built for selective expression of the Tg-ChEL domain. Objective 2 establishes an <em>in vitro</em> system using recombinant AChE as a reporter to enable future functional testing of ChEL domain mutations linked to congenital hypothyroidism. A deeper understanding of the functional role of the Tg’s ChEL domain could shed light on the spectrum of congenital hypothyroidism phenotypes, allowing for genotype-phenotype correlations for the future improvement of the disease diagnosis and treatment.</p>

Name thesis:degree_name

Master of Science (MS)

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year

2025

Author dc:creator

• Morales-Rodriguez, Berenice

Contributors dc:contributor

• Cintia E. Citterio, PhD
• Jennifer Totonchy, PhD
• Ajay Sharma, PhD

• thyroid
• ChEL domain
• thyroglobulin
• congenital hypothyroidism
• triiodothyronine
• acetylcholinesterase
• Congenital, Hereditary, and Neonatal Diseases and Abnormalities
• Endocrine System Diseases
• Other Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://digitalcommons.chapman.edu/pharmaceutical_sciences_theses/38

OAI identifier oai:identifier

oai:digitalcommons.chapman.edu:pharmaceutical_sciences_theses-1039