Genetics and phenomics of hypothyroidism and goiter due to TPO mutations

Thyroid peroxidase (TPO) is a heme binding protein localized on the apical membrane of the thyrocyte. TPO enzymatic activity is essential for thyroid hormonogenesis. Inactivating mutations form the molecular basis for a specific subtype of congenital hypothyroidism: thyroid dyshormonogenesis due to an iodide organification defect. The most common phenotype of this autosomal recessive disease is a total iodide organification defect, with severe and permanent hypothyroidism as a consequence. Currently 61 properly annotated mutations in the TPO gene have been reported, of which the majority are missense mutations. Functional data of most missense mutations is not available, making it necessary to revert to in silico methods for functional interpretation of mutations. We hypothesize that iodine status is the main phenomic modifier of TPO function.