HGNC Approved Gene Symbol: MUC6
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:1,012,823-1,036,718 (from NCBI)
The MUC6 gene encodes gastric mucin, a secreted glycoprotein that plays an essential role in epithelial cytoprotection from acid, proteases, pathogenic microorganisms, and mechanical trauma in the gastrointestinal tract (summary by Toribara et al., 1993).
By expression cloning, Toribara et al. (1993) isolated cDNAs coding for human gastric mucin. Expression of the gene was highest in the stomach and gallbladder, with weaker expression in the terminal ileum and right colon.
Reid and Harris (1998) used tissue in situ hybridization to study MUC6 gene expression in midtrimester human fetal gut. MUC6 mRNA was detected at low levels in the small intestine between 13 and 23 weeks' gestation. Abundant MUC6 mRNA was detected in gastric neck mucous cells, in contrast with MUC5AC (158373). MUC6 mRNA was present at high levels in pancreatic ductal epithelium throughout the midtrimester.
Rousseau et al. (2004) described the domain structure of human MUC6. MUC6 contains an N-terminal signal peptide, followed by several von Willebrand factor (VWF; 613160)-like domains, a large tandem repeat domain, and a C-terminal cystine knot domain.
Sekine et al. (2006) found that expression of HATH1 (ATOH1; 601461) was lost in 5 of 8 gastric cancer (GC) cell lines examined, whereas normal gastric mucosa expressed HATH1. Expression of the gastric mucin genes MUC6 and MUC5AC showed a correlation with that of HATH1 in most GC cell lines. Overexpression of Math1, a mouse HATH1 homolog, in GC cells strongly enhanced MUC6 and MUC5AC mRNA levels. RNA interference-mediated downregulation of HATH1 in GC cells led to decreased expression of the mucin genes. Sekine et al. (2006) concluded that HATH1 is a transcriptional regulator for MUC5AC and MUC6 in GC cells and that HATH1 loss may be involved in gastric carcinogenesis.
Rousseau et al. (2004) determined that the MUC6 gene contains 30 5-prime exons, 1 large central exon containing the tandem repeat domain, and 2 3-prime exons.
Kwon et al. (2010) noted that the MUC6 gene contains 35 exons and spans about 24 kb.
By fluorescence in situ hybridization, Toribara et al. (1993) mapped the MUC6 gene to chromosome 11p15.5-p15.4. Two other mucin genes (MUC2, 158370; MUC5AC, 158373) have been mapped to the 11p15 region, suggesting a clustering of secretory mucin genes.
Rousseau et al. (2004) determined that the MUC6 and MUC2 genes are located 38.5 kb apart in a head-to-head orientation within a gene complex on chromosome 11p15.5.
Kwon et al. (2010) identified 5 variable number tandem repeat (VNTR) minisatellite polymorphisms in the MUC6 gene, which they termed MS1 to MS5. MS1 and MS2 are located in the promoter region, MS3 in intron 1, MS4 in intron 8, and MS5 in intron 26. All were shown to be meiotically stable and subject to mendelian inheritance. Among 470 Korean patients with gastric cancer (137215) and 1,103 controls, there was no difference in the frequency of alleles for MS1 to MS4. However, there was a significant association between the rare MS5 short alleles and gastric cancer (p = 0.005; OR, 7.08), particularly for poorly differentiated gastric cancer. An analysis of 700 gastric cancer cases showed that those with short alleles lacked MUC6 gene expression. The MS5 region contained several putative transcription factor binding sites, and studies of transfected cells showed that the short MS5 allele significantly decreased reporter gene expression. These findings suggested that susceptibility to gastric cancer may be related to variation in MUC6 gene expression.
Kwon, J.-A., Lee, S.-Y., Ahn, E.-K., Seol, S.-Y., Kim, M. C., Kim, S. J., Kim, S. I., Chu, I.-S., Leem, S.-H. Short rare MUC6 minisatellites-5 (sic) alleles influence susceptibility to gastric carcinoma by regulating gene expression. Hum. Mutat. 31: 942-949, 2010. [PubMed: 20506113] [Full Text: https://doi.org/10.1002/humu.21289]
Reid, C. J., Harris, A. Developmental expression of mucin genes in the human gastrointestinal system. Gut 42: 220-226, 1998. [PubMed: 9536947] [Full Text: https://doi.org/10.1136/gut.42.2.220]
Rousseau, K., Byrne, C., Kim, Y. S., Gum, J. R., Swallow, D. M., Toribara, N. W. The complete genomic organization of the human MUC6 and MUC2 mucin genes. Genomics 83: 936-939, 2004. [PubMed: 15081123] [Full Text: https://doi.org/10.1016/j.ygeno.2003.11.003]
Sekine, A., Akiyama, Y., Yanagihara, K., Yuasa, Y. Hath1 up-regulates gastric mucin gene expression in gastric cells. Biochem. Biophys. Res. Commun. 344: 1166-1171, 2006. [PubMed: 16647036] [Full Text: https://doi.org/10.1016/j.bbrc.2006.03.238]
Toribara, N. W., Roberton, A. M., Ho, S. B., Kuo, W.-L., Gum, E., Hicks, J. W., Gum, J. R., Jr., Byrd, J. C., Siddiki, B., Kim, Y. S. Human gastric mucin: identification of a unique species by expression cloning. J. Biol. Chem. 268: 5879-5885, 1993. [PubMed: 7680650]