MUC1
protein-codingmucin 1, cell surface associated, the group of CD molecules|Mucins
Gene summary
This gene encodes a membrane-bound protein that is a member of the mucin family. Mucins are O-glycosylated proteins that play an essential role in forming protective mucous barriers on epithelial surfaces. These proteins also play a role in intracellular signaling. This protein is expressed on the apical surface of epithelial cells that line the mucosal surfaces of many different tissues including lung, breast stomach and pancreas. This protein is proteolytically cleaved into alpha and beta subunits that form a heterodimeric complex. The N-terminal alpha subunit functions in cell-adhesion and the C-terminal beta subunit is involved in cell signaling. Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas. This gene is known to contain a highly polymorphic variable number tandem repeats (VNTR) domain. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2011]
- PUM
- MCKD1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0020726
Submitter: ClinGen
*MUC1* was FIRST reported in relation to autosomal dominant tubulointerstitial kidney disease (ADTKD-*MUC1*; OMIM: 174000) in 2013 (Kirby et al, PMID: 23396133). ADTKD-*MUC1* is characterized by slowly progressive tubulointerstitial kidney disease that leads to end-stage renal disease (ESRD) between ages 20-70 years. Age of end-stage kidney disease is variable and the reasons for this variability are unclear. Patients with ADTKD-*MUC1* have a bland urinary sediment without proteinuria or hematuria. The kidney ultrasound shows changes that are commonly found in chronic kidney disease and in general is not helpful in making this diagnosis. The key diagnostic parameter is a family history of chronic kidney disease. There are no other primary clinical manifestations of this disease (PMIDs: 24509297, 23946964; 32450155, 36250282). *MUC1* contains within the coding region a domain of multiple variable-number tandem repeats called the "VNTR domain" [NC_000001.10:g.(155160963_155162030)]. Mutational analysis of the *MUC1* VNTR region is extremely difficult due to its repetitive nature and high guanine/cytosine content (>80%) (PMIDs: 31116938, 27157321). In approximately 95% of cases the ADTKD-*MUC1* pathogenic variant is the insertion of an extra cytosine within a heptanucleotide cytosine tract of a VNTR unit (PMIDs: 23396133, 29967284, 29217307). Less common is the insertion of a different nucleotide (e.g., adenine, guanine). At least 7 unique variants in the VNTR domain of *MUC1*, and one variant located immediately before the VNTR (PMIDs: 29156055, 29967284), have been reported in humans. *MUC1* pathogenic variants result in the creation of the +1 frameshifted MUC1 protein (MUC1-fs). Expression of MUC1-fs is toxic to kidney cells and is responsible for slowly progressive chronic kidney disease, the sole manifestation of this disorder. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least 600 individuals (from more than 300 families) and segregated with the disease (PMIDs: 24509297, 23946964, 29217307, 29156055, 32450155, 36250282;). *MUC1* pathogenic variants causing ADTKD-*MUC1* result in the creation of the same frameshifted protein (MUC1-fs). This protein accumulates within the endoplasmic reticulum Golgi intermediate compartment (ERGIC) (PMIDs: 31348885, 29967284, 36250282). In individuals with ADTKD-*MUC1*, MUC1-fs is found in all cell types normally expressing MUC1 (including breast, gastric mucosa, and lung) (PMID: 29967284); however, clinical manifestations of disease only occur in the kidney, where its deposition leads to accelerated apoptosis, tubular cell death, nephron dropout, and progressive chronic kidney disease. Summary of Experimental Evidence: 4 POINTS. This gene-disease association is supported by immunohistochemical studies of MUC1-fs in patient kidney biopsies, urine derived cells from patients, kidney organoids derived from ADTKD-*MUC1* patients and a MUC1-fs knock-in mouse model (PMIDs: 29967284, 29217307, 31348885). In summary, *MUC1* is definitively associated with autosomal dominant tubulointerstitial kidney disease due to *MUC1* frameshifting mutations mainly in the VNTR (ADTKD-*MUC1*). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cystic and Ciliopathy Disorders GCEP Working Group on 01/13/2021 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0020726
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0020726
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0020726
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0020726
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Renal transplant has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MUC1 variants in ClinVar
No annotated ClinVar phenotypes.
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript . Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 0 | |||||
| missense | 2 | 3 | 5 | |||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 4 | 3 | 0 | 7 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001018016.1 | 8 | Standard | |
| RefSeq | NP_001018017.1 | 8 | Standard | |
| RefSeq | NP_001037855.1 | 7 | Standard | |
| RefSeq | NP_001037856.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Interleukin-4 and 13 signaling
- Post-translational protein modification
- Dectin-2 family
- Metabolism of proteins
- C-type lectin receptors (CLRs)
Biological Process
- stimulatory C-type lectin receptor signaling pathway
- DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
- DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
- negative regulation of transcription by competitive promoter binding
- O-glycan processing
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- p53 binding
- transcription coregulator activity
- protein binding
Cellular Component
- nuclear chromatin
- extracellular space
- Golgi lumen
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000368395
- Coding exons
- 8
- Length
- 4408
- Individuals with no LoFs
- 125177
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125201
- p
- 0.0000958
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.23 | 325 | 268 | 1.21 | 0.0000153 | 3015 |
| Missense (PolyPhen) | 140 | 118.41 | 1.1824 | 1380 | ||
| Synonymous | -1.72 | 144 | 120 | 1.20 | 0.00000813 | 1069 |
| Loss of Function | 2.54 | 6 | 17.4 | 0.344 | 9.86e-7 | 180 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00044 | 0.00044 | rare |
| Finnish | 0.00018 | 0.00018 | rare |
| European (Non-Finnish) | 0.000080 | 0.000080 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.;
- Disease
- DISEASE: Note=MUC1/CA 15-3 is used as a serological clinical marker of breast cancer to monitor response to breast cancer treatment and disease recurrence (PubMed:20816948). Decreased levels over time may be indicative of a positive response to treatment. Conversely, increased levels may indicate disease progression. At an early stage disease, only 21% of patients exhibit high MUC1/CA 15-3 levels, that is why CA 15-3 is not a useful screening test. Most antibodies target the highly immunodominant core peptide domain of 20 amino acid (APDTRPAPGSTAPPAHGVTS) tandem repeats. Some antibodies recognize glycosylated epitopes. {ECO:0000269|PubMed:20816948}.; DISEASE: Medullary cystic kidney disease 1 (MCKD1) [MIM:174000]: A form of tubulointerstitial nephropathy characterized by formation of renal cysts at the corticomedullary junction. It is characterized by adult onset of impaired renal function and salt wasting resulting in end-stage renal failure by the sixth decade. {ECO:0000269|PubMed:23396133}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0717
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.545
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |