The Glu86 Residue in TBX4 Proves Critical for Human Lung Development

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• T-box transcription factors, including TBX4, regulate mesoderm development.
• TBX4 variants are linked to pulmonary arterial hypertension and lethal lung developmental disorders (LLDDs).
• Previous studies identified few TBX4 missense variants in LLDDs, all within the T-box domain.

Purpose of the Study:

• To report a recurrent pathogenic TBX4 substitution (Glu86Lys) in a patient with acinar dysplasia.
• To investigate the functional impact of TBX4 substitutions at residue 86 (Glu86Lys and Glu86Gln).
• To elucidate the role of TBX4 residue 86 in human lung development.

Main Methods:

• In silico analysis of TBX4 conformational changes due to Glu86Lys and Glu86Gln substitutions.
• Functional assays using TBX4 variants in fetal lung fibroblasts.
• Analysis of patient data linking TBX4 variants to LLDDs.

Main Results:

• The pathogenic substitution Glu86Lys was identified in an unrelated patient with acinar dysplasia.
• In silico predictions indicated loss of hydrogen bonds and altered DNA interaction for TBX4 variants.
• Functional assays confirmed the deleterious nature of TBX4 Glu86Lys and Glu86Gln variants.

Conclusions:

• Residue 86 of TBX4 is crucial for maintaining its structure and function in airway branching during lung development.
• Substitutions at TBX4 residue 86 may exert a dominant-negative effect, leading to acinar dysplasia and congenital alveolar dysplasia.
• These findings highlight the importance of TBX4 in preventing pediatric lung diseases.