CDC73 Gene - Cell Division Cycle 73
Parafibromin, a key component of the PAF1 complex involved in transcriptional regulation and tumor suppression
Gene Information Card
| Symbol | CDC73 |
|---|---|
| Full Name | Cell Division Cycle 73 |
| Gene Type | Protein coding |
| Chromosomal Location | 1q31.2 |
| NCBI Gene ID | 79577 ncbi.nlm.nih.gov/gene/79577 |
| Ensembl ID | ENSG00000134371 |
| UniProt ID | Q6P1J9 |
| OMIM ID | 607393 |
| HGNC ID | 16783 |
| Aliases | HRPT2, HPTJT, C1orf28, FIHP, parafibromin |
Description
The CDC73 gene encodes parafibromin, a protein component of the PAF1 (RNA polymerase II-associated factor 1) complex. Parafibromin is involved in transcriptional elongation, histone modification, and cell cycle regulation. It functions as a tumor suppressor, and germline loss-of-function mutations cause hyperparathyroidism-jaw tumor syndrome (HPT-JT), an autosomal dominant disorder predisposing to parathyroid adenoma/carcinoma and ossifying fibromas of the jaw. Somatic mutations in CDC73 are also found in sporadic parathyroid carcinomas and other cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT) | Germline loss-of-function mutations in CDC73 lead to haploinsufficiency or complete loss of parafibromin, disrupting PAF1 complex-mediated transcriptional regulation and promoting parathyroid cell proliferation. | OMIM #145001; multiple families with segregating mutations |
| Parathyroid Carcinoma | Somatic inactivating mutations (frameshift, nonsense) or loss of heterozygosity at 1q31.2 result in loss of parafibromin expression, driving malignant transformation. | ClinVar; COSMIC; ~70% of sporadic parathyroid carcinomas harbor CDC73 mutations |
| Familial Isolated Hyperparathyroidism (FIHP) | Heterozygous germline CDC73 mutations can present as FIHP without jaw tumors, indicating phenotypic variability. | OMIM #145000; case reports |
| Breast Cancer | Reduced parafibromin expression or somatic mutations may contribute to tumor progression, though evidence is limited. | COSMIC; limited functional studies |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Parathyroid gland | Not available (GTEx nTPM) | High (immunohistochemistry) |
| Kidney | Not available (GTEx nTPM) | Moderate |
| Heart | Not available (GTEx nTPM) | Low |
| Testis | Not available (GTEx nTPM) | Moderate |
| Thyroid | Not available (GTEx nTPM) | Moderate |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | Not available | Endogenous expression confirmed by western blot |
| HeLa | Not available | Endogenous expression confirmed |
| MCF7 | Not available | Reduced expression in some breast cancer lines |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.679_680delAG | Frameshift deletion | Common in HPT-JT | Loss of function; truncated parafibromin |
| c.1A>G (p.Met1?) | Missense (start loss) | Rare | Loss of translation initiation |
| c.165_166insA | Frameshift insertion | Reported in parathyroid carcinoma | Loss of function |
| c.700C>T (p.Arg234*) | Nonsense | Recurrent in HPT-JT | Premature stop; loss of function |
Mutation functional classification
Loss of Function (LOF)
Majority of CDC73 mutations are loss-of-function (nonsense, frameshift, splice-site, large deletions), leading to reduced or absent parafibromin protein. This impairs PAF1 complex function and contributes to tumorigenesis.
Gain of Function (GOF)
No gain-of-function mutations have been reported for CDC73.
Dominant Negative (DN)
No dominant-negative mutations have been characterized; the mechanism is primarily haploinsufficiency or complete loss.
View complete mutation data：
Gene Ontology (GO)
| • RNA polymerase II transcription elongation factor activity | • Chromatin binding |
| • Transcription elongation from RNA polymerase II promoter | • Histone modification |
| • Cell cycle regulation | • Negative regulation of cell proliferation |
| • PAF1 complex |
Pathways
• PAF1 complex (Reactome: R-HSA-5250924)
• RNA Polymerase II Transcription Elongation (Reactome: R-HSA-75955)
• Transcriptional regulation by the PAF1 complex (KEGG: map03020)
Protein Summary
Parafibromin is a 531-amino acid protein (UniProt Q6P1J9) that localizes to the nucleus and is a core component of the PAF1 complex. It interacts with RNA polymerase II and other elongation factors to facilitate transcriptional elongation and co-transcriptional histone modifications (e.g., H2B monoubiquitination, H3K4 and H3K79 methylation). Parafibromin also plays roles in cell cycle progression, Wnt/β-catenin signaling, and DNA damage response. Loss of parafibromin expression is a hallmark of parathyroid carcinoma and HPT-JT-associated tumors.
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