ArticleThe Journal of allergy and clinical immunology2025
Gain-of-function variants in SMAD4 compromise respiratory epithelial function.
Article in The Journal of allergy and clinical immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed.
- SMAD4-BPIFA1 Axis Governs Airway Antiviral Defense in Myhre Syndrome.Biomolecules · 2026Article
- Neo-Cysteine Molecular Glues for Targeting Mutated SMAD4 Protein.Angewandte Chemie (International ed. in English) · 2026Article
- Identification and characterization of a TGF-β-independent SMAD4-NFATc1-STAT3 regulatory axis.Journal of molecular cell biology · 2026Article
- Navigating Drug Discovery for Myhre Syndrome: The Complexity of a Multisystemic Rare Disease.American journal of medical genetics. Part C, Seminars in medical genetics · 2025Review
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
backgroundMyhre syndrome is an exceedingly rare yet increasingly diagnosed genetic disorder arising from germline variants in the SMAD4 gene. Its core manifestation is the progression of stiffness and fibrosis across multiple organs. Individuals with Myhre syndrome exhibit a propensity for upper respiratory tract remodeling and infections. The molecular and cellular mechanisms underlying this phenotype remain unclear.
objectiveWe sought to investigate how SMAD4 pathogenic variants associated with Myhre syndrome affect SMAD4 protein levels, activation, and physiological functions in patient-derived nasal epithelial cells.
methodsClinical observations were conducted on a cohort of 47 patients recruited at Massachusetts General Hospital from 2016 to 2023. Nasal epithelial basal cells were isolated and cultured from inferior turbinate brushings of healthy subjects (n = 8) and patients with Myhre syndrome (n = 3; SMAD4-Ile500Val, Arg496Cys, and Ile500Thr). Transcriptomic analysis and functional assays were performed to assess SMAD4 levels, transcriptional activity, and epithelial cell host defense functions, including cell proliferation, mucociliary differentiation, and bacterial elimination.
resultsClinical observations revealed a prevalent history of otitis media and sinusitis among most individuals with Myhre syndrome. Analyses of nasal epithelial cells indicated that SMAD4 mutations do not alter SMAD4 protein stability or upstream regulatory SMAD phosphorylation but enhance signaling transcriptional activity, supporting a gain-of-function mechanism, likely attributable to increased protein-protein interaction of the SMAD complex. Consequently, Myhre syndrome nasal basal cells exhibit reduced potential in cell proliferation and mucociliary differentiation. Furthermore, Myhre syndrome nasal epithelia are impaired in bacterial killing.
conclusionsCompromised innate immunity originating from epithelial cells in Myhre syndrome may contribute to increased susceptibility to upper respiratory tract infections.
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