Gain-of-function variants in SMAD4 compromise respiratory epithelial function.

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Otorhinolaryngology

Background:

• Myhre syndrome is a rare genetic disorder caused by SMAD4 gene variants, characterized by organ fibrosis and respiratory issues.
• The underlying molecular mechanisms for respiratory complications in Myhre syndrome are not well understood.

Purpose of the Study:

• To investigate the impact of SMAD4 variants in Myhre syndrome on protein levels, activation, and function in patient-derived nasal epithelial cells.
• To elucidate the cellular mechanisms contributing to upper respiratory tract infections in Myhre syndrome.

Main Methods:

• Collected clinical data from 47 Myhre syndrome patients and 8 healthy controls.
• Isolated and cultured nasal epithelial basal cells from patients and controls for transcriptomic and functional analyses.
• Assessed SMAD4 levels, transcriptional activity, cell proliferation, mucociliary differentiation, and bacterial elimination.

Main Results:

• Myhre syndrome patients frequently experience otitis media and sinusitis.
• SMAD4 mutations enhance transcriptional activity, suggesting a gain-of-function mechanism.
• Nasal epithelial cells in Myhre syndrome show reduced proliferation, impaired mucociliary differentiation, and diminished bacterial killing capacity.

Conclusions:

• Compromised innate immunity in epithelial cells of Myhre syndrome patients contributes to their susceptibility to upper respiratory tract infections.
• Understanding these cellular defects offers potential therapeutic targets for respiratory complications in Myhre syndrome.