One Novel and Two Recurrent THRB Mutations Associated with Resistance to Thyroid Hormone: Structure-based...

Area of Science:

• Endocrinology
• Genetics
• Computational Biology

Background:

• Inactivating mutations in the THRB gene, encoding thyroid hormone receptor beta (TRβ), lead to resistance to thyroid hormone (RTH).
• Over 100 THRB mutations have been identified in RTH patients, predominantly affecting the ligand-binding domain.
• Accurate assessment of THRB mutation pathogenicity is crucial for diagnosing and understanding RTH.

Purpose of the Study:

• To describe the clinical and molecular findings of three families with RTH.
• To introduce and validate a novel computational method for predicting the pathogenicity of THRB mutations.
• To evaluate the feasibility of this structure-based prediction system for missense THRB mutations.

Main Methods:

• Clinical and molecular data from three RTH families were analyzed.
• A novel computational mutation prediction method was developed using 3D structural data of the TRβ-T3 complex.
• The prediction system's accuracy was assessed using known pathogenic and benign THRB variations, achieving 80% sensitivity and 93% specificity.

Main Results:

• Three families presented with RTH, harboring one novel (p.I431M) and two recurrent (p.R320H, p.R383C) THRB mutations.
• The developed computational method predicted all three identified mutations as deleterious.
• The prediction system demonstrated high accuracy in distinguishing pathogenic from benign THRB variations.

Conclusions:

• The novel structure-based computational method is a prompt, inexpensive, and feasible tool for evaluating the pathogenicity of missense THRB mutations.
• This approach can aid in the diagnosis and understanding of resistance to thyroid hormone.
• Further application of this method can accelerate the identification and characterization of genetic causes of RTH.