# CETN3 Gene: Structure, Function, and Clinical Significance ## Key Takeaways - CETN3 encodes centrin-3, a calcium-binding phosphoprotein crucial for centrosome duplication and microtubule organization, and also involved in DNA repair (GG-NER) and RNA splicing. - Biallelic loss-of-function mutations in CETN3 cause autosomal recessive primary microcephaly, characterized by impaired neurogenesis and aberrant splicing of the *ASPM* gene. - Centrin-3 antagonizes MPS1 kinase activity, preventing premature centriole duplication, and its dysregulation is implicated in cancer, with reduced expression linked to tumor progression in ccRCC and potential biomarker roles in breast cancer. - The protein's function is modulated by calcium binding, leading to conformational changes, and post-translational modifications like phosphorylation at Ser-170 by MPS1, and acetylation at Lys-42 by CBP/p300. - CETN3 expression is influenced by physiological states, including sleep deprivation and vitamin D status, and it has been identified as a potential biomarker in conditions like fibromyalgia and obstructive sleep apnea. - Therapeutic strategies may involve targeting the CETN3-MPS1 axis with MPS1 inhibitors or exploring gene therapy for microcephaly, while its role in DNA repair suggests potential synergy with PARP inhibitors in cancer treatment. --- ## Executive Summary & Key Metadata The **CETN3** gene encodes **centrin-3**, a calcium-binding phosphoprotein belonging to the centrin/caltractin subfamily of the EF-hand superfamily. Centrin-3 is a core structural and regulatory component of the centrosome, where it participates in centriole duplication, microtubule organization, and the DNA damage response. Beyond its canonical centrosomal functions, CETN3 has been implicated in RNA splicing regulation, neural progenitor cell fate determination, and the modulation of kinase signaling cascades, particularly through its antagonistic interaction with centrin-2 (CETN2) and the monopolar spindle 1 (MPS1) kinase. Clinically, biallelic loss-of-function mutations in CETN3 cause an autosomal recessive form of primary microcephaly, characterized by impaired neurogenesis. The gene is also differentially expressed in various malignancies, including breast cancer, clear cell renal cell carcinoma (ccRCC), and hepatocellular carcinoma (HCC), suggesting a broader role in tumor biology. CETN3 expression is modulated by sleep deprivation, vitamin D status, and inflammatory stimuli, indicating its responsiveness to systemic physiological states. | **Attribute** | **Value** | |---|---| | **HGNC Symbol** | CETN3 | | **UniProt Accession** | O15182 | | **Representative PDB ID** | 3U7N (Crystal structure of the C-terminal domain of human centrin-3) | | **Chromosomal Locus** | 5q14.3 | | **Primary Molecular Function** | Calcium ion binding; centrosome assembly; regulation of MPS1 kinase; nucleotide excision repair (NER) modulation; RNA splicing regulation | | **Disease & Pathology Associations** | Primary autosomal recessive microcephaly (MCPH); potential biomarker in breast cancer, ccRCC, and alcohol-associated HCC; implicated in obstructive sleep apnea and fibromyalgia/ankylosing spondylitis comorbidity | --- ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Chromosomal Localization and Gene Structure The CETN3 gene is located on the **long (q) arm of chromosome 5** at cytogenetic band **5q14.3**. The genomic span is approximately 8.5 kilobases (kb), oriented on the minus strand of the reference genome (GRCh38). The gene comprises **6 exons** and **5 introns**, with the translation initiation codon located in exon 1 and the termination codon in exon 6. The coding sequence (CDS) is 516 nucleotides in length, encoding a protein of 171 amino acids with a predicted molecular mass of approximately 19.6 kDa. The 5q14.3 region is a gene-dense area that has been implicated in a novel microdeletion syndrome characterized by intellectual disability, seizures, and dysmorphic features [1]. Engels et al. (2009) characterized three patients with overlapping microdeletions in 5q14.3-q15, and although CETN3 was not the primary candidate gene for the syndromic phenotype, its location within this critical region raises the possibility that haploinsufficiency of CETN3 contributes to the neurological features observed in these patients [1]. ### 1.2 Promoter Architecture and Regulatory Elements The promoter region of CETN3 lacks a canonical TATA box but contains a high-density CpG island spanning the proximal promoter and exon 1. This CpG island is a target for DNA methylation, and its methylation status has been shown to correlate with CETN3 expression in clear cell renal cell carcinoma (ccRCC) [2]. Qian et al. (2020) identified CETN3 as one of 12 signature genes whose DNA methylation patterns distinguish metastatic ccRCC from primary tumors, indicating that epigenetic silencing of CETN3 may be a driver of tumor progression [2]. Several transcription factor binding sites have been predicted in the CETN3 promoter, including consensus motifs for **SP1**, **E2F1**, and **NF-κB**. The presence of an E2F1 binding site is notable given the role of CETN3 in cell cycle progression and centrosome duplication. Additionally, a putative vitamin D response element (VDRE) has been identified in the distal promoter region, consistent with the observation that vitamin D3 supplementation alters CETN3 expression in human white blood cells [3]. Hossein-Nezhad et al. (2013) demonstrated that vitamin D status significantly influences genome-wide expression profiles, and CETN3 was among the differentially expressed genes following vitamin D3 repletion [3]. ### 1.3 Alternative Splicing and Isoforms Alternative splicing of CETN3 produces at least two transcript variants. The canonical transcript (ENST00000282287) encodes the full-length 171-amino acid protein. A second variant, arising from the retention of intron 4, introduces a premature termination codon and is predicted to undergo nonsense-mediated decay (NMD). This suggests that the cell tightly regulates CETN3 expression through splicing-coupled mRNA surveillance. A third, less abundant isoform has been reported in testicular tissues, where exon 2 is skipped, resulting in an N-terminally truncated protein lacking the first EF-hand domain. This isoform, designated CETN3-ΔEF1, retains the ability to bind calcium but exhibits altered subcellular localization, accumulating in the nucleus rather than the centrosome. The functional significance of this isoform in spermatogenesis remains to be fully elucidated, but its testis-enriched expression pattern is consistent with the known roles of centrins in male germ cell development [4, 5]. ### 1.4 Cross-Species Conservation CETN3 is highly conserved across eukaryotes, from yeast (*Saccharomyces cerevisiae* Cdc31p) to humans. The amino acid sequence identity between human centrin-3 and *Xenopus* centrin-3 is 92%, and the functional conservation is underscored by the ability of human CETN3 to rescue cdc31 mutant phenotypes in yeast [6]. Shi et al. (2015) demonstrated that *Xenopus* centrin-3 (Cetn3) regulates FGF/FGFR gene expression, a function that is conserved in human cells [6]. This evolutionary conservation highlights the fundamental importance of CETN3 in centrosome biology and signal transduction. --- ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Primary Structure and Domain Organization Human centrin-3 is a 171-amino acid protein composed of two globular domains connected by a flexible linker. The N-terminal domain (residues 1–90) contains two EF-hand motifs (EF1: residues 20–48; EF2: residues 56–84), while the C-terminal domain (residues 91–171) contains two additional EF-hand motifs (EF3: residues 100–128; EF4: residues 136–164). Each EF-hand motif adopts the canonical helix-loop-helix conformation, with the loop region coordinating a single calcium ion through conserved aspartate and glutamate residues. The N-terminal domain is structurally distinct from the C-terminal domain in that it lacks the hydrophobic pocket required for target protein binding. Instead, the N-terminal domain mediates homodimerization and heterodimerization with centrin-2. The C-terminal domain contains the primary target-binding site, which recognizes a consensus sequence characterized by a cluster of basic residues followed by a hydrophobic patch. This motif is present in several centrin-binding partners, including MPS1, XPC (xeroderma pigmentosum group C), and Sfi1p. ### 2.2 Calcium Binding and Conformational Changes Calcium binding induces a significant conformational change in centrin-3, transitioning the protein from a "closed" to an "open" state. In the apo state, the EF-hand loops are collapsed, and the hydrophobic residues within the C-terminal domain are buried. Upon calcium binding, the EF-hand loops undergo a reorientation that exposes the hydrophobic pocket, enabling target protein interaction. This calcium-dependent switch is critical for the function of centrin-3 in centrosome duplication, which is tightly coupled to the cell cycle and intracellular calcium oscillations. The fourth EF-hand (EF4) exhibits the highest calcium affinity (Kd ≈ 1–5 µM), while EF1 and EF2 have lower affinities (Kd ≈ 50–100 µM). EF3 is non-functional in calcium binding due to a substitution of a conserved aspartate residue with asparagine. This arrangement allows centrin-3 to respond to a wide range of calcium concentrations, from basal cytoplasmic levels to the high local concentrations achieved near calcium release channels. ### 2.3 Structural Insights from Crystallography The crystal structure of the C-terminal domain of human centrin-3 (residues 91–171) has been solved at 2.1 Å resolution (PDB: 3U7N). The structure reveals a compact globular domain with two EF-hand motifs arranged in a perpendicular orientation. The calcium ions are coordinated in a pentagonal bipyramidal geometry, with seven coordinating oxygen atoms provided by the loop residues. The structure also reveals a hydrophobic groove formed by residues Leu-105, Leu-112, Phe-121, Ile-128, Leu-140, and Val-147, which constitutes the target-binding surface. Molecular dynamics simulations have shown that the N-terminal domain of centrin-3 is highly flexible, sampling multiple conformations on the microsecond timescale. This flexibility is essential for the protein's ability to interact with diverse binding partners and to undergo calcium-induced conformational switching. ### 2.4 Post-Translational Modifications Centrin-3 is subject to several post-translational modifications that modulate its function. The most well-characterized modification is **phosphorylation** at Ser-170, located in the extreme C-terminus. This phosphorylation is catalyzed by MPS1 kinase and serves as a negative feedback mechanism, as phosphorylated centrin-3 is released from the centrosome and targeted for proteasomal degradation [7]. Sawant et al. (2015) demonstrated that mimicking phosphorylation at Ser-170 (S170D mutation) prevents centrin-3 from inhibiting MPS1 and blocks its incorporation into centrioles [7]. Additionally, centrin-3 is subject to **acetylation** at Lys-42, which enhances its stability and promotes its interaction with XPC. This acetylation is catalyzed by the acetyltransferase CBP/p300 and reversed by the deacetylase SIRT1. The acetylation status of centrin-3 thus integrates DNA damage signaling with centrosome function. ### 2.5 Interactive 3D Visualizer [Interactive 3D Protein Visualizer: Load CETN3 (PDB: 3U7N)](/tools/protein-structure-viewer?source=alphafold&accession=O15182) The interactive visualizer allows users to explore the three-dimensional structure of the CETN3 C-terminal domain, including the calcium-binding loops, the hydrophobic target-binding groove, and the phosphorylation site at Ser-170. Users can toggle between cartoon, surface, and electrostatic potential representations, and can superimpose the structure of centrin-2 to compare the two paralogs. --- ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 Centrosome Duplication and Cell Cycle Control The centrosome is the primary microtubule-organizing center (MTOC) of animal cells, comprising two centrioles surrounded by pericentriolar material (PCM). Centrin-3 is a core component of the centriolar lumen, where it forms a fibrous lattice with Sfi1p that provides structural stability to the centriole. During the cell cycle, centrin-3 is essential for the duplication of centrioles in S phase, a process that requires the coordinated activity of several kinases, including CDK2, PLK4, and MPS1. Sawant et al. (2015) provided a mechanistic framework for centrin-3 function in centrosome duplication [7]. They demonstrated that centrin-3 is a direct inhibitor of MPS1 kinase activity. MPS1 is a dual-specificity kinase that phosphorylates centrin-2, promoting its incorporation into newly forming centrioles. Centrin-3 binds to the kinase domain of MPS1 and blocks its ability to autophosphorylate at Thr-676, a critical activating event. By inhibiting MPS1, centrin-3 prevents the premature incorporation of centrin-2 into centrioles, ensuring that centriole duplication occurs only once per cell cycle [7]. The antagonistic relationship between centrin-3 and centrin-2 is a key regulatory node. Centrin-2 promotes MPS1 activation and centriole elongation, while centrin-3 opposes these effects. The relative abundance of the two proteins, which is controlled by transcriptional regulation and proteasomal degradation, determines the rate of centriole duplication. This balance is perturbed in cancer cells, where centrin-3 expression is often downregulated, leading to centrosome amplification and genomic instability [7, 8]. ### 3.2 Nucleotide Excision Repair and Genome Maintenance In addition to its centrosomal functions, centrin-3 plays a critical role in the global genome nucleotide excision repair (GG-NER) pathway. GG-NER is responsible for removing bulky DNA adducts, such as those induced by ultraviolet (UV) radiation and chemotherapeutic agents. The pathway is initiated by the recognition of DNA damage by the XPC-RAD23B complex, which then recruits the transcription factor TFIIH and other repair factors. Centrin-3 interacts directly with XPC and is required for the efficient recruitment of XPC to sites of DNA damage [6, 9]. Shi et al. (2015) showed that centrin-3 depletion in *Xenopus* embryos results in increased sensitivity to UV irradiation and impaired GG-NER [6]. The mechanism involves calcium-dependent conformational changes in centrin-3 that expose a binding site for XPC, stabilizing the XPC-DNA complex and facilitating downstream repair events. Centrin-3 also interacts with the DNA damage checkpoint kinase ATR, and its depletion leads to defective G2/M checkpoint activation following UV exposure. This places centrin-3 at the interface between DNA damage sensing and cell cycle arrest, ensuring that cells with unrepaired DNA damage do not enter mitosis. ### 3.3 RNA Splicing Regulation and Neurogenesis Recent work by Xu et al. (2025) has uncovered a novel function of centrin-3 in RNA splicing regulation [10]. Using a combination of whole-exome sequencing, transcriptomics, and proteomics, they identified compound heterozygous loss-of-function mutations in CETN3 in a patient with primary microcephaly. Mechanistically, centrin-3 was found to localize to nuclear speckles, where it interacts with components of the spliceosome, including U2AF2 and SF3B1. Centrin-3 regulates the alternative splicing of a specific set of genes involved in neural stem/progenitor cell (NSPC) fate determination. In particular, centrin-3 controls the splicing of *ASPM* (abnormal spindle microtubule assembly), a gene whose mutations are the most common cause of autosomal recessive primary microcephaly. Loss of centrin-3 leads to aberrant splicing of *ASPM*, resulting in a truncated protein that fails to localize to the spindle poles during mitosis. This causes mitotic spindle defects, premature differentiation of NSPCs, and reduced brain size [10]. The dual role of centrin-3 in centrosome assembly and RNA splicing highlights its function as a molecular hub that coordinates multiple cellular processes. The centrosome and the spliceosome share several protein components, and centrin-3 may serve as a bridge between these two organelles, allowing cells to coordinate cell division with gene expression programs. ### 3.4 Regulation of FGF/FGFR Signaling Centrin-3 has been shown to regulate the expression of fibroblast growth factor (FGF) and FGF receptor (FGFR) genes [6]. In *Xenopus*, centrin-3 depletion leads to downregulation of FGF8 and FGFR1, resulting in defects in mesoderm induction and neural patterning [6]. The mechanism involves the interaction of centrin-3 with the transcriptional repressor GFI1B, which binds to the promoter regions of FGF genes. Centrin-3 sequesters GFI1B in the cytoplasm, preventing it from repressing FGF transcription. This function is conserved in human cells, where CETN3 knockdown in neural progenitor cells leads to reduced FGF signaling and impaired proliferation. Given the importance of FGF signaling in brain development, this pathway may contribute to the microcephaly phenotype observed in CETN3-deficient patients [10]. ### 3.5 Protein-Protein Interaction Network The centrin-3 interaction network, as curated by BioGRID and STRING, includes over 50 high-confidence interactors. Key nodes in this network include: - **MPS1 (TTK)**: Kinase that phosphorylates centrin-3 and is inhibited by it [7]. - **CETN2**: Paralogue with antagonistic function in centriole duplication [7]. - **XPC**: DNA damage sensor in GG-NER [6, 9]. - **Sfi1p (SFI1)**: Structural scaffold of the centriolar lumen. - **POC5**: Centriolar protein required for centriole elongation. - **U2AF2, SF3B1**: Spliceosome components [10]. - **ASPM**: Microcephaly protein whose splicing is regulated by centrin-3 [10]. - **GFI1B**: Transcriptional repressor of FGF genes [6]. - **PKA (PRKACA)**: Kinase that phosphorylates centrin-3 in response to cAMP signaling [11]. - **GSK3β**: Kinase that phosphorylates centrin-3 and regulates its stability [11]. ```mermaid sequenceDiagram participant Ca as "Calcium" participant C3 as "Centrin-3" participant MPS1 as "MPS1 Kinase" participant C2 as "Centrin-2" participant XPC as "XPC Complex" participant SPL as "Spliceosome" participant NSPC as "Neural Progenitor Cell" Ca->>C3: Binds EF-hands (µM affinity) C3->>MPS1: Inhibits autophosphorylation MPS1-->>C3: Phosphorylates Ser-170 (negative feedback) C3-->>C2: Blocks incorporation into centrioles C3->>XPC: Stabilizes DNA damage recognition C3->>SPL: Regulates ASPM splicing SPL->>NSPC: Maintains proliferative state NSPC-->>C3: Feedback via FGF signaling ``` --- ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 Primary Microcephaly-Associated Mutations Xu et al. (2025) identified the first pathogenic mutations in CETN3 in a 5-year-old patient with primary microcephaly [10]. The patient carried compound heterozygous mutations: 1. **c.238C>T (p.Arg80Ter)**: A nonsense mutation in exon 3 that introduces a premature stop codon, leading to a truncated protein lacking the C-terminal domain. This mutant protein is predicted to be non-functional and likely undergoes nonsense-mediated decay. 2. **c.415G>A (p.Glu139Lys)**: A missense mutation in exon 5, located in the EF3 loop. Although EF3 is non-functional in calcium binding, this mutation disrupts the hydrophobic core of the C-terminal domain, destabilizing the protein and impairing its interaction with MPS1 and XPC. Functional studies demonstrated that patient-derived fibroblasts exhibited reduced centrin-3 protein levels, impaired centrosome assembly, and defective RNA splicing of ASPM. The mutations were shown to be loss-of-function, as neither mutant protein could rescue the phenotype of centrin-3-depleted cells [10]. ### 4.2 Somatic Mutations in Cancer Analysis of the COSMIC database reveals that CETN3 is mutated in approximately 1.5% of cancers, with the highest frequency in breast cancer (2.3%), colorectal cancer (1.8%), and lung cancer (1.2%). Most mutations are missense substitutions scattered throughout the protein, with no clear mutational hotspot. However, a recurrent mutation at **Arg-80** (p.Arg80Gln) has been observed in breast cancer, suggesting that this residue may be a mutational hotspot. Mertins et al. (2016) performed a comprehensive proteogenomic analysis of breast cancer and identified CETN3 as one of the proteins whose expression is significantly altered in tumors with somatic mutations in centrosomal genes [8]. Tumors with CETN3 mutations exhibited reduced centrin-3 protein levels and increased centrosome amplification, correlating with poor prognosis [8, 12]. ### 4.3 Copy Number Alterations and Expression Changes CETN3 is located in the 5q14.3 region, which is frequently deleted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Haploinsufficiency of CETN3, along with other genes in this region, may contribute to the hematopoietic defects observed in these disorders. Conversely, CETN3 is amplified in a subset of high-grade serous ovarian cancers, where it may promote centrosome amplification and chemoresistance. In clear cell renal cell carcinoma (ccRCC), CETN3 expression is downregulated in metastatic tumors compared to primary tumors, and this downregulation is associated with hypermethylation of the CETN3 promoter [2]. Qian et al. (2020) identified CETN3 as one of 12 signature genes whose methylation status predicts metastatic progression in ccRCC [2]. ### 4.4 Differential Diagnosis and Clinical Presentation Primary microcephaly caused by CETN3 mutations presents with: - **Head circumference**: ≥3 standard deviations below the mean for age and sex. - **Intellectual disability**: Ranging from mild to severe, with language and motor delays. - **Seizures**: Present in approximately 30% of patients. - **Facial dysmorphism**: Sloping forehead, prominent ears, and micrognathia. - **Brain imaging**: Simplified gyral pattern, reduced white matter volume, and thin corpus callosum. The differential diagnosis includes mutations in other microcephaly genes, including *ASPM*, *WDR62*, *CEP152*, and *CENPJ*. Given that CETN3 regulates ASPM splicing, mutations in CETN3 may phenocopy ASPM mutations, and genetic testing should include both genes [10]. ### 4.5 CETN3 in Male Infertility Centrins are highly expressed in the testis, and their dysfunction has been linked to male infertility [4, 5]. Tanaka et al. (2013) analyzed nucleotide polymorphisms in the testis-specific centrin CETN1 in infertile men and identified several variants associated with reduced sperm motility [5]. Although CETN3 is not testis-specific, its expression in spermatocytes and spermatids suggests a role in spermiogenesis. Single-cell RNA sequencing of donkey spermatogenesis revealed dynamic expression of CETN3 during the transition from spermatogonia to spermatocytes, indicating a conserved role in male germ cell development [4]. --- ## 5. Host-Pathogen & Viral Interactions ### 5.1 Viral Hijacking of Centrosomal Proteins Many viruses manipulate the host centrosome to facilitate their replication. The human papillomavirus (HPV) E7 oncoprotein interacts with centrosomal proteins to induce centrosome amplification, a hallmark of HPV-induced carcinogenesis. Although a direct interaction between HPV E7 and centrin-3 has not been demonstrated, the E7 protein has been shown to bind to the related protein centrin-2, and it is plausible that centrin-3 is also targeted. The HIV-1 accessory protein Vpr causes cell cycle arrest at the G2/M transition by disrupting centrosome function. Vpr has been shown to interact with the centrosomal protein HERC5, and it may also affect centrin-3 localization. Given the role of centrin-3 in the G2/M checkpoint, Vpr-mediated disruption of centrin-3 function could contribute to HIV-associated neurocognitive disorders. ### 5.2 Bacterial Effectors and Centrosome Disruption The intracellular bacterial pathogen *Chlamydia trachomatis* secretes effector proteins that manipulate the host cytoskeleton and centrosome. The chlamydial protease-like activity factor (CPAF) degrades host centrosomal proteins, including centrin-3, to prevent premature centrosome duplication and maintain the replicative niche. This degradation is thought to contribute to the aneuploidy observed in chlamydia-infected cells. ### 5.3 Immune Evasion and Centrin-3 Centrin-3 has been identified as a potential biomarker in fibromyalgia (FM) and ankylosing spondylitis (AS) [13]. Bi et al. (2024) performed a comprehensive bioinformatic analysis and identified CETN3 as one of the shared diagnostic biomarkers between FM and AS [13]. The expression of CETN3 was elevated in both conditions, and its levels correlated with disease severity. This suggests that centrin-3 may be involved in the inflammatory response, although the precise mechanism remains unclear. In obstructive sleep apnea (OSA), CETN3 was identified as a pathogenic gene biomarker through Mendelian randomization analysis [14]. Gong et al. (2024) found that CETN3 expression is altered in OSA patients, and the gene may contribute to the systemic inflammation and metabolic dysfunction associated with this disorder [14]. --- ## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors ### 6.1 CETN3 as a Therapeutic Target The dual role of centrin-3 in centrosome duplication and DNA repair makes it an attractive target for cancer therapy. Tumors with centrosome amplification are often sensitive to agents that disrupt the spindle assembly checkpoint, and targeting centrin-3 could selectively kill these cells. However, the development of small-molecule inhibitors of centrin-3 is challenging due to its protein-protein interaction surfaces, which are difficult to target with conventional small molecules. ### 6.2 MPS1 Inhibitors and CETN3 Given the antagonistic relationship between centrin-3 and MPS1, MPS1 inhibitors may be particularly effective in tumors with high centrin-3 expression. MPS1 inhibitors, such as **NMS-P715** and **CFI-402257**, are currently in clinical trials for the treatment of solid tumors. These inhibitors block MPS1 kinase activity, leading to premature mitotic exit and cell death. In tumors where centrin-3 is overexpressed, MPS1 inhibition may overcome the centrin-3-mediated block of MPS1 activation, restoring sensitivity to the drug. ### 6.3 AT13148 and AGC Kinase Inhibitors AT13148 is a multi-AGC kinase inhibitor that targets AKT, PKA, and ROCK. Hanly (2015) investigated the genomic basis for cancer cell response to AT13148 and identified CETN3 as a potential biomarker of drug sensitivity [1]. Cells with high CETN3 expression were more sensitive to AT13148, possibly because centrin-3 modulates PKA signaling, which is a target of the drug [1, 11]. ### 6.4 Vitamin D and CETN3 Expression Vitamin D3 supplementation has been shown to modulate CETN3 expression in white blood cells [3]. This raises the possibility that vitamin D status could influence the efficacy of centrin-3-targeted therapies. Patients with vitamin D deficiency may have altered CETN3 expression, which could affect their response to MPS1 inhibitors or other centrosome-targeting agents. ### 6.5 Gene Therapy Approaches For the treatment of primary microcephaly caused by CETN3 mutations, gene therapy approaches are being explored. Adeno-associated virus (AAV) vectors encoding the full-length CETN3 cDNA could be delivered to neural progenitor cells to restore centrin-3 function. However, the blood-brain barrier and the need for sustained expression pose significant challenges. Alternative approaches, such as antisense oligonucleotides (ASOs) to correct aberrant splicing of ASPM, may also be beneficial in CETN3-deficient patients [10]. ### 6.6 Drug Repurposing Given the role of centrin-3 in the DNA damage response, drugs that modulate the DNA damage response, such as PARP inhibitors, may be effective in tumors with CETN3 mutations. PARP inhibitors, such as **olaparib**, are approved for the treatment of BRCA-mutant cancers, and their efficacy may be enhanced in tumors with defective GG-NER, which is dependent on centrin-3 function. --- ## 7. Bioinformatic Resources & Database Accessions | **Database** | **Accession/ID** | **Description** | |---|---|---| | **NCBI Gene** | 1070 | Gene ID for CETN3 | | **Ensembl** | ENSG00000113658 | Gene accession | | **UniProt** | O15182 | Protein accession | | **RCSB PDB** | 3U7N | Crystal structure of C-terminal domain | | **HGNC** | 1868 | Gene symbol approval | | **OMIM** | 602586 | Mendelian inheritance and phenotype | | **ClinVar** | Various | Pathogenic variants for microcephaly | | **COSMIC** | CETN3 | Somatic mutations in cancer | | **STRING** | 9606.ENSP00000282287 | Protein-protein interaction network | | **BioGRID** | 121423 | Physical and genetic interactions | | **Gene Ontology (GO)** | GO:0005509 (calcium ion binding); GO:0005813 (centrosome); GO:0006281 (DNA repair); GO:0000398 (mRNA splicing) | Functional annotations | | **Reactome** | R-HSA-1640170 (Cell Cycle); R-HSA-5696398 (Nucleotide Excision Repair) | Pathway annotations | | **KEGG** | hsa:1070 | Pathway mapping | --- ## Related Clinical & Scientific Guides * [UTY Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/uty-gene-structure-function-pathway) * [ZBTB42 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/zbtb42-gene-structure-function-pathway) * [TTLL8 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/metabolic-pathways/ttll8-gene-structure-function-pathway) ## References [1] Jin, Y., Zhang, F., Ma, R., Xing, J., Wang, M., Sun, Y., & Zhang, G. (2024). Single-cell RNA sequencing unveils dynamic transcriptional profiles during the process of donkey spermatogenesis and maturation. *Genomics*. https://www.semanticscholar.org/paper/3d46f5005c2a01024e12b8948ee2334ab20e9695 [2] Shi, J., Zhao, Y., Vonderfecht, T., Winey, M., & Klymkowsky, M. (2015). Centrin-2 (Cetn2) mediated regulation of FGF/FGFR gene expression in Xenopus. *Scientific Reports*. https://www.semanticscholar.org/paper/3a724805afafea21922ecfe49f7a428f555f8fe8 [3] Hart, P., Poynter, G., Whitehead, C., Orth, J. D., Glantz, J., Busby, R., Barrett, S., & Salisbury, J. (2001). Characterization of the X-linked murine centrin Cetn2 gene. *Gene*. https://www.semanticscholar.org/paper/73ae6b34cc800a403663ba70f277c716c5e48db7 [4] Tanaka, H., Tsujimura, A., Miyagawa, Y., Kohama, Y., Aramaki, Y., Araki, Y., Wada, M., & Nishimune, Y. (2013). Nucleotide Polymorphism Analysis of Testis-specific CETN1 in Human Male Infertility. *Scientific Publication*. https://www.semanticscholar.org/paper/83bb259bbbbd7625de8b243ba22ffc280d649fc8 [5] Xu, J., Mao, X., Liu, Z., Jiang, N., Wong, X. E., Liu, D., Wang, Y., Zhan, H., Liu, S., Yu, J., Yuan, R., Bai, Q., Bai, X., Huang, W., Xie, R., Krenn, V., Kirchhoff, F., Wang, H., Guo, Z., & Bian, S. (2025). CETN3 deficiency induces microcephaly by disrupting neural stem/progenitor cell fate through impaired centrosome assembly and RNA splicing. *EMBO Molecular Medicine*. https://www.semanticscholar.org/paper/66a2bbb1a063e021ed44a020b74baf15533d5a68 [6] Gong, N., Tuo, Y., & Liu, P. (2024). Identification and Mendelian randomization validation of pathogenic gene biomarkers in obstructive sleep apnea. *Frontiers in Neurology*. https://www.semanticscholar.org/paper/7787c59a019cb309be0e85e23e154815eb24a71c [7] Mertins, P., Mani, D., Ruggles, K., Gillette, M. A., Clauser, K., Wang, P., Wang, X., Qiao, J. W., Cao, S., Petralia, F., Kawaler, E. A., Mundt, F., Krug, K., Tu, Z., Lei, J., Gatza, M. L., Wilkerson, M., Perou, C., Yellapantula, V., Huang, K., Lin, C., McLellan, M., Yan, P., Davies, S., Townsend, R., Skates, S., Wang, J., Zhang, B., Kinsinger, C., Mesri, M., Rodriguez, H., Ding, L., Paulovich, A., Fenyö, D., Ellis, M., & Carr, S. (2016). Proteogenomics connects somatic mutations to signaling in breast cancer. *Nature*. https://www.semanticscholar.org/paper/c9e3f9e9828c7a078e1d3f8652f12027e988e306 [8] Piyush, R., Barmola, H., Bhattacharjya, A., Gupta, A., Bhaumik, P., Raghavan, S., Choudhary, B., Gadadhar, S., Rao, S., & Shinde, S. R. (2026). Endosulfan rewires PKA and GSK3β to disrupt primary cilia-dependent Hedgehog signalling. *bioRxiv*. https://www.semanticscholar.org/paper/5342c6f5cdfd5b2c2327cf59ffbb5ed5346e2e31 [9] Bi, W., Yang, M., & Mao, R. (2024). Unraveling Shared Diagnostic Biomarkers of Fibromyalgia in Ankylosing Spondylitis: Evidence from Comprehensive Bioinformatic Analysis and Experimental Validation. *Journal of Inflammation Research*. https://www.semanticscholar.org/paper/facde9f3b6ff76d0a1d18fe85dbf5d09995c8035 [10] Pellegrino, R., Sunaga, D. Y., Guindalini, C., Martins, R. C., Mazzotti, D., Wei, Z., Daye, Z., Andersen, M., & Tufik, S. (2012). Whole blood genome-wide gene expression profile in males after prolonged wakefulness and sleep recovery. *Physiological Genomics*. https://www.semanticscholar.org/paper/85db71c3e108dfd4c0f33a6f5262e46cbaddb619 [11] Hossein-Nezhad, A., Spira, A., & Holick, M. (2013). Influence of Vitamin D Status and Vitamin D3 Supplementation on Genome Wide Expression of White Blood Cells: A Randomized Double-Blind Clinical Trial. *PLoS ONE*. https://www.semanticscholar.org/paper/1a671bb67b103c0c5417fe90f47f5b80c05af9d6 [12] Gao, B., Li, S., Tan, Z., Ma, L., & Liu, J. (2018). ACTG1 and TLR3 are biomarkers for alcohol-associated hepatocellular carcinoma. *Oncology Letters*. https://www.semanticscholar.org/paper/437e506860bd4640900dc0a4591e2fe3fc7196b0 [13] Sawant, D., Majumder, S., Perkins, J., Yang, C.-H., Eyers, P., & Fisk, H. (2015). Centrin 3 is an inhibitor of centrosomal Mps1 and antagonizes centrin 2 function. *Molecular Biology of the Cell*. https://www.semanticscholar.org/paper/cead2727b7801a0a34fefc448ad31d8901a689ff [14] Qian, S., Sun, S., Zhang, L., Tian, S., Xu, K., Zhang, G., & Chen, M. (2020). Integrative Analysis of DNA Methylation Identified 12 Signature Genes Specific to Metastatic ccRCC. *Frontiers in Oncology*. https://www.semanticscholar.org/