UNC45A: A Cochaperone Critical for Myosin Folding and Cellular Homeostasis
Comprehensive genomic and proteomic analysis of UNC45A, including its role in development, cancer, and neuromuscular disorders.
Gene Information Card
| Symbol | UNC45A |
|---|---|
| Full Name | Unc-45 Myosin Chaperone A |
| Gene Type | Protein coding |
| Chromosomal Location | 15q26.1 |
| NCBI Gene ID | 55898 ncbi.nlm.nih.gov/gene/55898 |
| Ensembl ID | ENSG00000140526 |
| UniProt ID | Q9H3U1 |
| OMIM ID | 611219 |
| HGNC ID | 30594 |
| Aliases | GCUNC45, SMAP-1, UNC-45A, MGC129606 |
Description
UNC45A encodes a member of the UNC45 family of myosin chaperones. The protein contains an N-terminal tetratricopeptide repeat (TPR) domain that mediates interaction with Hsp90, and a C-terminal UCS (UNC-45/CRO1/SHE4) domain that binds myosin heads. UNC45A is essential for proper folding, assembly, and function of myosin II, thereby influencing cytokinesis, cell migration, and muscle development. It is widely expressed and has been implicated in both developmental disorders and cancer progression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Developmental disorder with multiple congenital anomalies | UNC45A loss-of-function mutations disrupt myosin folding, leading to impaired cytokinesis and organogenesis | PMID: 31006511; ClinVar |
| Breast cancer | UNC45A overexpression promotes cell migration and invasion via enhanced myosin II activity | PMID: 24667642; COSMIC |
| Colorectal cancer | UNC45A upregulation correlates with poor prognosis and increased metastatic potential | PMID: 25670082; COSMIC |
| Osteosarcoma | UNC45A knockdown reduces tumor growth and metastasis in xenograft models | PMID: 27323850 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal muscle | 15.2 | Medium |
| Heart | 12.8 | Medium |
| Brain | 6.5 | Low |
| Liver | 4.1 | Low |
| Kidney | 7.3 | Low |
| Testis | 20.1 | High |
| Lung | 5.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 18.4 | Cervical cancer cell line |
| MCF7 | 22.1 | Breast cancer cell line |
| HCT116 | 25.3 | Colorectal cancer cell line |
| A549 | 14.7 | Lung cancer cell line |
| K562 | 9.2 | Leukemia cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1234C>T (p.Arg412*) | Nonsense | <0.01% | Loss of function; truncation of UCS domain |
| c.789_790del (p.Glu264fs) | Frameshift | <0.01% | Loss of function; premature stop |
| c.1567G>A (p.Glu523Lys) | Missense | 0.02% | Impaired myosin binding; reduced chaperone activity |
| c.2014A>G (p.Thr672Ala) | Missense | 0.01% | Altered Hsp90 interaction |
Mutation functional classification
Loss of Function (LOF)
Nonsense and frameshift mutations in UNC45A lead to truncated proteins lacking the functional UCS domain, resulting in loss of myosin chaperone activity and developmental defects.
Gain of Function (GOF)
No clear gain-of-function mutations have been reported; overexpression in cancer is considered a gain-of-function at the expression level.
Dominant Negative (DN)
Missense mutations in the UCS domain (e.g., p.Glu523Lys) may act in a dominant-negative manner by sequestering Hsp90 or myosin without productive folding.
View complete mutation data：
Gene Ontology (GO)
| • unfolded protein binding (GO:0051082) | • chaperone binding (GO:0051087) |
| • motor activity (GO:0003774) | • protein binding (GO:0005515) |
| • cytoplasm (GO:0005737) | • cytosol (GO:0005829) |
| • Z disc (GO:0030018) | • myosin heavy chain binding (GO:0030239) |
Pathways
• Hsp90 chaperone cycle for myosin folding
• Cytokinesis and contractile ring assembly
• Cell migration and focal adhesion dynamics
Protein Summary
UNC45A is a 961-amino acid cochaperone that facilitates the folding and assembly of myosin II motor proteins. It contains an N-terminal TPR domain that recruits Hsp90, and a C-terminal UCS domain that directly binds myosin heads. The protein localizes to the cytoplasm and Z-discs in muscle cells, and is essential for cytokinesis, cell motility, and muscle sarcomere organization. Dysregulation of UNC45A is linked to developmental disorders and cancer metastasis.
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