Alternative titles; symbols
HGNC Approved Gene Symbol: MUC5B
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:1,223,066-1,262,172 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | {Pulmonary fibrosis, idiopathic, susceptibility to} | 178500 | Autosomal dominant | 3 |
Mucins are high molecular mass, highly glycosylated macromolecules that are the major components of mucus secretions. MUC5B is a salivary mucin that is thought to contribute to the lubricating and viscoelastic properties of whole saliva. It is composed of 14.9% protein, 78.1% carbohydrate, and 7% sulfate (Troxler et al., 1995).
Troxler et al. (1995) cloned a cDNA encoding MUC5B, called MG1 by them, by screening a human sublingual gland cDNA expression library with anti-MUC5B antibodies. By Northern blot analysis, MUC5B is expressed primarily in the sublingual gland.
Desseyn et al. (1997) isolated MUC5B genomic sequence. They found that the central exon encodes a predicted 3,570-amino acid peptide containing 19 subdomains that can be grouped into 4 larger composite units referred to as 'superrepeats'. Since MUC5B and the related proteins MUC2 and MUC5AC are clustered within chromosome 11p15.5, suggesting that they are members of a multigene family. Desseyn et al. (1997) reported that the region 3-prime of the large central exon of MUC5B is composed of 18 exons and spans about 10.7 kb. This region encodes a predicted 808-amino acid peptide containing 6 subdomains; the last 5 are cysteine-rich and are similar to MUC2, MUC5AC, and von Willebrand factor (VWF; 613160). Desseyn et al. (1997) noted that MUC5B is expressed mainly in bronchus glands and also in submaxillary glands, endocervix, gallbladder, and pancreas. Desseyn et al. (1998) reported that the region upstream of the large central exon of MUC5B is composed of 29 exons and spans 15.1 kb. This region encodes 1,283 amino acid residues. The full-length 5,662-amino acid MUC5B protein has a calculated molecular mass of 600 kD.
Gallbladder mucin has been shown to play a central role in the pathogenesis of cholesterol gallstone disease. Keates et al. (1997) cloned a MUC5B cDNA from a human gallbladder cDNA expression library and showed that MUC5B is a major mucin in the gallbladder. By Northern blot analysis, hybridization of MUC5B cDNA probes to gallbladder and trachea mRNA resulted in a broad 1- to 9-kb signal. Keates et al. (1997) stated that this polydisperse hybridization pattern is typical of that observed with other mucin mRNAs and may result from the shearing of very large transcripts.
Using real-time RT-PCR, Moehle et al. (2006) found that MUC5B was highly expressed in adult trachea and colon and in fetal lung. Expression was lower in adult salivary gland, followed by thyroid, mammary gland, uterus, lung, and stomach. Weak expression was detected in pancreas, and none was detected in other tissues.
Desseyn et al. (1998) determined that the MUC5B gene contains 48 exons.
Pigny et al. (1995) stated that they had evidence that the locus corresponding to 3 groups of partial tracheobronchial mucin cDNAs that was mapped to chromosome 11p15 and given the symbol MUC5 in fact comprises 2 distinct genes, which they provisionally called MUC5B and MUC5AC (158373).
Endocervical epithelium expresses mRNA of 3 of the large gel-forming mucins, MUC5AC, MUC5B, and MUC6 (158374), with mRNA of MUC5B predominating. Because mucin protein levels may be regulated posttranscriptionally, measurement of MUC5B protein levels with cycle were needed for correlation to mRNA levels. Gipson et al. (2001) developed a polyclonal antibody specific to MUC5B. They used the MUC5B antibody along with a standard cervical mucin isolated in an enzyme-linked immunosorbent assay to determine the relative amount of MUC5B in samples of human cervical mucus taken through the menstrual cycle. A peak of MUC5B occurred in human cervical mucus collected at midcycle, compared with mucus from early or late in the cycle. This peak in MUC5B content coincided with the midcycle change in mucus character, suggesting that MUC5B may be important to sperm transit to the uterus.
By microarray analysis, Moehle et al. (2006) found coordinated downregulation of mucins, including MUC5B, in ileum and colon of Crohn disease and ulcerative colitis (IBD; see 266600) patients compared with controls. They identified an NF-kappa-B (see 164011)-binding site in the MUC5B promoter and showed that activation of the NF-kappa-B signaling pathway by inflammatory cytokine TGF-beta (TGFB1; 190180) upregulated MUC5B mRNA expression 2-fold.
Roy et al. (2014) showed that mouse Muc5b, but not Muc5ac, is required for mucociliary clearance (MCC), for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL23A; 605580) production was reduced in Muc5b-null mice. By contrast, in mice that transgenically overexpressed Muc5b, macrophage functions improved. Mucous phenotypes in asthma (600807) and chronic obstructive pulmonary disease (COPD; 606963) were thought to be driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. Roy et al. (2014) concluded that by distinguishing a specific role for Muc5b in MCC and by determining its impact on bacterial infections and inflammation in mice, their results provided a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
Seibold et al. (2011) identified a single-nucleotide polymorphism (SNP) in the MUC5B promoter, rs35705950 (600770.0001), in which the minor allele is associated with dramatically increased risk of idiopathic pulmonary fibrosis or familial interstitial pneumonia. Seibold et al. (2011) found that expression of the gene among unaffected subjects carrying at least 1 copy variant allele was 37.4 times as high as it was among unaffected subjects homozygous for the wildtype allele. Zhang et al. (2011) also found association of this SNP with idiopathic pulmonary fibrosis, confirming the results of Seibold et al. (2011).
Using a genomewide linkage scan, Seibold et al. (2011) detected linkage between idiopathic interstitial pneumonia (178500) and a 3.4-Mb region of chromosome 11p15 in 82 families. They then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. The minor allele (T) of SNP rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, p = 1.2 x 10(-15); allelic association with idiopathic pulmonary fibrosis, p = 2.5 x 10(-37)). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% CI, 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (p less than 0.001). The variant allele of rs35705950 was associated with upregulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wildtype allele, p less than 0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis.
Zhang et al. (2011) confirmed the findings of Seibold et al. (2011). They studied 341 cases with idiopathic pulmonary fibrosis from the University of Pittsburgh, University of Chicago, and 802 controls from the same 2 centers and found a strong association of the minor allele at rs35705950 with pulmonary fibrosis, with a P value of 7.6 x 10(-40). The odds ratios for idiopathic pulmonary fibrosis in subjects who were heterozygous or homozygous for the minor allele of rs35705950 were 5.9 (95% CI, 4.4 to 7.8) and 9.7 (95% CI, 4.7 to 19.9), respectively.
Hunninghake et al. (2013) performed a blinded assessment of interstitial lung abnormalities in 2,633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). One hundred seventy-seven of these individuals (7%) had interstitial lung abnormalities. Those individuals were more likely to have shortness of breath, chronic cough, and reduced measures of total lung and diffusion capacity. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% CI, 2.0 to 3.9; p less than 0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; p less than 0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association.
Using a discovery population and multiple validation populations, Juge et al. (2018) tested the association of the MUC5B promoter variant rs35705950 in 620 patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), 614 patients with RA without ILD, and 5448 unaffected controls. Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% CI, 2.8 to 5.2; p = 9.7 x 10(-17)). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; p = 4.7 x 10(-35)) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; p = 1.3 x 10(-49)). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; p = 7.4 x 10(-5)), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography. However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. Juge et al. (2018) concluded that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging.
Desseyn, J.-L., Aubert, J.-P., van Seuningen, I., Porchet, N., Laine, A. Genomic organization of the 3-prime region of the human mucin gene MUC5B. J. Biol. Chem. 272: 16873-16883, 1997. [PubMed: 9201995] [Full Text: https://doi.org/10.1074/jbc.272.27.16873]
Desseyn, J.-L., Buisine, M. P., Porchet, N., Aubert, J.-P., Laine, A. Genomic organization of the human mucin gene MUC5B, cDNA and genomic sequences upstream of the large central exon. J. Biol. Chem. 273: 30157-30164, 1998. [PubMed: 9804771] [Full Text: https://doi.org/10.1074/jbc.273.46.30157]
Desseyn, J.-L., Guyonnet-Duperat, V., Porchet, N., Aubert, J.-P., Laine, A. Human mucin gene MUC5B, the 10.7-kb large central exon encodes various alternate subdomains resulting in a super-repeat: structural evidence for a 11p15.5 gene family. J. Biol. Chem. 272: 3168-3178, 1997. [PubMed: 9013550] [Full Text: https://doi.org/10.1074/jbc.272.6.3168]
Gipson, I. K., Moccia, R., Spurr-Michaud, S., Argueso, P., Gargiulo, A. R., Hill, J. A., III, Offner, G. D., Keutmann, H. T. The amount of MUC5B in cervical mucus peaks at midcycle. J. Clin. Endocr. Metab. 86: 594-600, 2001. [PubMed: 11158014] [Full Text: https://doi.org/10.1210/jcem.86.2.7174]
Hunninghake, G. M., Hatabu, H., Okajima, Y., Gao, W., Dupuis, J., Latourelle, J. C., Nishino, M., Araki, T., Zazueta, O. E., Kurugol, S., Ross, J. C., Estepar, R. S. J., and 9 others. MUC5B promoter polymorphism and interstitial lung abnormalities. New Eng. J. Med. 368: 2192-2200, 2013. [PubMed: 23692170] [Full Text: https://doi.org/10.1056/NEJMoa1216076]
Juge, P.-A., Lee, J. S., Ebstein, E., Furukawa, H., Dobrinskikh, E., Gazal, S., Kannengiesser, C., Ottaviani, S., Oka, S., Tohma, S., Tsuchiya, N., Rojas-Serrano, J., and 60 others. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. New Eng. J. Med. 379: 2209-2219, 2018. [PubMed: 30345907] [Full Text: https://doi.org/10.1056/NEJMoa1801562]
Keates, A. C., Nunes, D. P., Afdhal, N. H., Troxler, R. F., Offner, G. D. Molecular cloning of a major human gall bladder mucin: complete C-terminal sequence and genomic organization of MUC5B. Biochem. J. 324: 295-303, 1997. [PubMed: 9164870] [Full Text: https://doi.org/10.1042/bj3240295]
Moehle, C., Ackermann, N., Langmann, T., Aslanidis, C., Kel, A., Kel-Margoulis, O., Schmitz-Madry, A., Zahn, A., Stremmel, W., Schmitz, G. Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease. J. Molec. Med. 84: 1055-1066, 2006. [PubMed: 17058067] [Full Text: https://doi.org/10.1007/s00109-006-0100-2]
Pigny, P., Pratt, W. S., Laine, A., Leclercq, A., Swallow, D. M., Nguyen, V. C., Aubert, J. P., Porchet, N. The MUC5AC gene: RFLP analysis with the Jer58 probe. Hum. Genet. 96: 367-368, 1995. [PubMed: 7649560] [Full Text: https://doi.org/10.1007/BF00210427]
Roy, M. G., Livraghi-Butrico, A., Fletcher, A. A., McElwee, M. M., Evans, S. E., Boerner, R. M., Alexander, S. N., Bellinghausen, L. K., Song, A. S., Petrova, Y. M., Tuvim, M. J., Adachi, R., and 31 others. Muc5b is required for airway defence. Nature 505: 412-416, 2014. [PubMed: 24317696] [Full Text: https://doi.org/10.1038/nature12807]
Seibold, M. A., Wise, A. L., Speer, M. C., Steele, M. P., Brown, K. K., Loyd, J. E., Fingerlin, T. E., Zhang, W., Gudmundsson, G., Groshong, S. D., Evans, C. M., Garantziotis, S., and 17 others. A common MUC5B promoter polymorphism and pulmonary fibrosis. New Eng. J. Med. 364: 1503-1512, 2011. [PubMed: 21506741] [Full Text: https://doi.org/10.1056/NEJMoa1013660]
Troxler, R. F., Offner, G. D., Zhang, F., Iontcheva, I., Oppenheim, F. G. Molecular cloning of a novel high molecular weight mucin (MG1) from human sublingual gland. Biochem. Biophys. Res. Commun. 217: 1112-1119, 1995. [PubMed: 8554565] [Full Text: https://doi.org/10.1006/bbrc.1995.2884]
Zhang, Y., Noth, I., Garcia, J. G. N., Kaminski, N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. (Letter) New Eng. J. Med. 364: 1576-1577, 2011. [PubMed: 21506748] [Full Text: https://doi.org/10.1056/NEJMc1013504]