Abstract
ObjectiveBased on mutations in PAX8 is associated with thyroid dysgenesis. We aim to identify and characterize PAX8 mutations in a large cohort of congenital hypothyroidism(CH) from thyroid dysgenesis in Chinese population.MethodsWe screened 453 unrelated Chinese patients with CH from thyroid dysgenesis for PAX8 mutations by sequencing the whole coding regions of PAX8 on genomic DNA isolated from blood. Cell transfection assays using various vector constructs and induced mutagenesis as well as electrophoretic mobility shift assays were used to investigate the effects of selected mutations on the transcribing and binding activities of PAX8 at the promoters of target genes for thyroglobulin (TG) and thyroperoxidase (TPO).ResultsFive PAX8 mutations were found, yielding a mutation prevalence of 5/453 (1.1%). We selected two mutations in the critical paired domain of PAX8 and generated mutants D94N and G41V. We demonstrated G41V was unable to bind the specific sequence in the promoters of TG and TPO and activate them. D94N could bind to TG and TPO promoters and normally activate the TG promoter transcription but not the TPO promoter transcription. We also demonstrated a dominant negative role of the PAX8 mutants in impairing the function of the wild-type PAX8.ConclusionWe for the first time documented the prevalence and characterized the function of PAX8 mutations in CH in Chinese population. The study specifically demonstrated the role of novel mutations D94N and G41V in impairing the function of PAX8, providing further evidence for genetic PAX8 defects as a disease mechanism in CH.
Highlights
Congenital hypothyroidism (CH), characterized by elevated thyroid-stimulating hormone (TSH) resulting from reduced thyroid function at birth, is the most common congenital endocrine disease, with an incidence of 1 in 2000–4000 newborns [1]
The study demonstrated the role of novel mutations D94N and G41V in impairing the function of paired box transcription factor 8 (PAX8), providing further evidence for genetic PAX8 defects as a disease mechanism in CH
The other two variants were PAX8 c.1064C>T/p.A355V and PAX8 c.-26G>A in two unrelated athyroid patients with thyroid dysgenesis; given the thyroid agenesis in the affected patients, it is possible that the former may impair the PAX8 protein function since it is a non-sense mutation and the latter may affect the PAX8 gene expression since it is in the promoter area
Summary
Congenital hypothyroidism (CH), characterized by elevated thyroid-stimulating hormone (TSH) resulting from reduced thyroid function at birth, is the most common congenital endocrine disease, with an incidence of 1 in 2000–4000 newborns [1]. Thanks to the early screening strategies in recent decades, CH is a highly identifiable and treatable condition at an early patient age. It is currently still an important cause of mental retardation originated in infants [2]. Thyroid dysgenesis (TD), characterized by development defects of the thyroid gland, accounts for 85% of cases of CH and presents with varying clinical phenotypes. The thyroid gland in thyroid dysgenesis is not visible (agenesis) in 35–40% of cases, small and ectopically located in 30–45% of cases, and eutopically located but severely reduced in size (hypoplasia) in 5% of cases [2]. Mutations in the genes for TSH receptor [4], NKX2-1 (thyroid transcription factor 1) [5], thyroid transcription factor 2 [6], and paired box transcription factor 8 (PAX8) [7] have been identified in some patients with various forms of thyroid dysgenesis
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