Screening and Functional Analysis of TPO Gene Mutations in Patients With Congenital Hypothyroidism

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• Congenital hypothyroidism (CH) is often caused by thyroid hormone synthesis disorders.
• Thyroid peroxidase (TPO) gene mutations are the most frequent pathogenic variants identified in CH.
• The clinical significance of some identified TPO variants remains uncertain.

Purpose of the Study:

• To investigate the pathogenicity of a novel TPO variant of uncertain significance (VUS), p.K78Q.
• To analyze the impact of the TPO p.K78Q variant on thyroid hormone synthesis and thyroid axis gene expression.

Main Methods:

• Whole-exome sequencing (WES) was performed on 54 children diagnosed with CH.
• Functional analysis of the TPO p.K78Q variant was conducted using a zebrafish model.
• Thyroid axis gene expression was assessed following functional analysis.

Main Results:

• The TPO p.K78Q variant was identified in the study cohort.
• Functional analysis revealed that the TPO p.K78Q variant caused developmental defects in zebrafish.
• The variant disrupted thyroid axis gene expression, leading to decreased expression of tg, dio1, dio2, trβ, nis, ttr and increased expression of tshβ, trα.

Conclusions:

• The novel TPO p.K78Q variant is pathogenic and contributes to CH.
• The findings clarify the significance of a previously uncertain TPO variant.
• This study highlights the importance of functional analysis in diagnosing CH caused by TPO mutations.