MUC5B – Interstitial Lung Disease

MUC5B encodes a secreted gel-forming mucin critical for airway mucus homeostasis. Common and rare variants in MUC5B have been implicated in both adult and pediatric forms of interstitial lung disease (ILD), with evidence spanning family segregation, case series, and mechanistic studies. This summary evaluates the strength of the genetic and functional data supporting a gene-disease association for MUC5B and ILD (MONDO:0015925). ClinGen criteria yield a Moderate classification based on multiple unrelated probands, segregation in autosomal recessive pedigrees, and concordant experimental data.

1. Genetic Evidence

Autosomal recessive inheritance is supported by two unrelated families in which affected siblings harbor biallelic MUC5B coding variants. In one family, a homozygous nonsense variant, c.16861G>T (p.Glu5621Ter), was identified in two siblings with severe neonatal ILD ([PMID:33526882]). In a second family, two siblings with severe early-onset ILD carried compound heterozygous MUC5B missense changes. Overall, four probands across two families demonstrate segregation of rare coding variants with disease.

2. Variant Spectrum

Rare loss-of-function and missense MUC5B variants underlie congenital ILD phenotypes. The recurrent homozygous c.16861G>T (p.Glu5621Ter) variant has been observed in unrelated neonates with alveolar simplification and interstitial fibrosis. Compound heterozygous missense variants (e.g., c.14936>C (p.Ile4979Thr)) further extend the spectrum. No dominant coding variants have been consistently observed in familial adult ILD.

3. Common Risk Variant in Adult ILD

A promoter variant, rs35705950, strongly predisposes to adult idiopathic pulmonary fibrosis and RA-ILD, acting as a risk allele rather than a Mendelian variant. In transgenic mice overexpressing the human rs35705950 allele, bleomycin-induced fibrosis was paradoxically attenuated, suggesting complex dosage-dependent effects ([PMID:39329706]).

4. Functional and Expression Studies

Single-cell RNA-seq and receptor–ligand modeling revealed that MUC5B variants alter epithelial–mesenchymal communication and promote aberrant IL-6 and amphiregulin signaling in fibrotic lung epithelia ([PMID:36291184]). eQTL and mQTL studies co-localize rs35705950 with increased MUC5B expression and altered methylation in patient lung tissue, supporting a gain-of-function mechanism ([PMID:35816432]).

5. Conflicting Evidence

No studies to date have refuted the association of rare MUC5B coding variants with congenital ILD. Multivariate analyses in RA-ILD cohorts have suggested that MUC5B risk effects may interact with age, smoking, and sex, but no clear contradictions have emerged.

6. Integration and Clinical Utility

Together, autosomal recessive segregation of coding variants in congenital ILD and risk effects of a common promoter allele in adult ILD form a coherent mechanism whereby MUC5B dysregulation promotes lung fibrosis. Additional large-scale population studies and functional validations could elevate the classification to Strong. Key Take-home: MUC5B variant testing informs diagnosis and risk stratification across both pediatric and adult ILD presentations.

References

• Scientific reports • 2021 • Genetic variants of small airways and interstitial pulmonary disease in children. PMID:33526882
• Cells • 2024 • Bleomycin-Induced Pulmonary Fibrosis in Transgenic Mice Carrying the Human MUC5B rs35705950 Variant. PMID:39329706
• Cells • 2022 • Dysregulated Cell-Cell Communication Characterizes Pulmonary Fibrosis. PMID:36291184
• American journal of respiratory and critical care medicine • 2022 • Colocalization of Gene Expression and DNA Methylation with Genetic Risk Variants Supports Functional Roles of MUC5B and DSP in Idiopathic Pulmonary Fibrosis. PMID:35816432

Evidence Based Scoring (AI generated)