Functional study of three cases with novel TBX19 variants

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is a rare autosomal recessive disorder.
• TBX19 gene mutations are a known cause of CIAD.
• Understanding TBX19 variants is crucial for diagnosing and managing CIAD.

Purpose of the Study:

• Identify novel TBX19 variants in CIAD patients.
• Elucidate the structural, functional, and protein-level mechanisms of these variants.
• Enhance clinical understanding and management of CIAD.

Main Methods:

• Clinical data from three CIAD children were analyzed.
• Multiple sequence alignment and five pathogenicity prediction algorithms were employed.
• Protein structure modeling (AlphaFold 3), immunoblotting, and luciferase reporter assays were performed.

Main Results:

• Five TBX19 variants were identified, including two novel ones (c.856C>T and c.377C>T).
• Predicted and confirmed loss-of-function effects on TBX19 protein, altering interactions and protein structure.
• TBX19 variants significantly suppressed pro-opiomelanocortin (POMC) transcriptional activity.

Conclusions:

• Five TBX19 loss-of-function variants, two novel, were identified in CIAD patients.
• These findings expand the known spectrum of TBX19 variants associated with CIAD.
• Provides new perspectives on the pathophysiological mechanisms of CIAD.