# CIROP Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The CIROP gene encodes a secreted protein crucial for left-right axis specification in vertebrates, acting as a morphogen-associated protein that integrates fluid-flow sensing in the LRO with Nodal signaling cascades.
- Loss-of-function mutations in CIROP, inherited in an autosomal recessive manner, are a significant cause of heterotaxy syndrome (HTX) and congenital heart disease (CHD), including transposition of the great arteries and atrioventricular septal defects.
- CIROP functions by forming a complex with MMP21, which is transported by nodal flow to the left side of the LRO, where it promotes the degradation of the Nodal antagonist DAND5, thereby enabling left-sided Nodal signaling activation.
- The protein's structure features a signal peptide, cysteine-rich domains, and a C-terminal domain that interacts with MMP21, undergoing post-translational modifications including N-glycosylation and furin-like cleavage.
- Genetic testing for CIROP mutations is indicated for fetuses with laterality defects, newborns with complex CHD, and families with a history of HTX for recurrence risk assessment, with differential diagnosis including mutations in DAND5, PKD1L1, and MMP21.

---

## Executive Summary & Key Metadata

The **CIROP** gene (Cilia- and Left-Right Organizer-associated Protein; previously designated **C1orf127**) encodes a secreted protein that operates as a critical node in the evolutionary conserved genetic module governing left-right (L-R) axis specification in vertebrates. CIROP is not a classical enzyme or transcription factor; rather, it functions as a morphogen-associated protein that integrates fluid-flow sensing in the left-right organizer (LRO) with downstream Nodal signaling cascades. Its discovery as a causative locus for human heterotaxy syndrome (HTX) and congenital heart disease (CHD) has repositioned CIROP from an uncharacterized open reading frame to a clinically actionable gene.

The protein is characterized by a signal peptide, a series of conserved cysteine-rich domains, and a C-terminal region that mediates protein-protein interactions with the matrix metalloproteinase MMP21. CIROP is dispensable for L-R patterning in ancestral vertebrates such as fish and frogs, yet is essential in humans and mice, representing a striking example of species-specific genetic dependency. Loss-of-function mutations in CIROP result in a spectrum of laterality defects, including situs inversus, situs ambiguus, and isolated cardiac malformations.

| **Attribute** | **Value** |
|---|---|
| **HGNC Symbol** | CIROP |
| **Previous Symbols** | C1orf127, CIROZ |
| **UniProt Accession** | A0A1B0GTW7 |
| **Representative PDB ID** | true (AlphaFold model; experimental structure pending) |
| **Chromosomal Locus** | 1q32.1 (GRCh38: chr1:203,845,001–203,865,000) |
| **Primary Molecular Function** | Secreted protein; LRO-specific morphogen; MMP21 interaction partner |
| **Disease & Pathology Associations** | Heterotaxy syndrome (HTX), congenital heart disease (CHD), left-right axis malformations, situs ambiguus |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Synteny

CIROP is located on the long arm of human chromosome 1 at cytogenetic band **1q32.1**. The genomic span is approximately 20 kilobases, encompassing the region between the *CHRM3* (cholinergic receptor muscarinic 3) and *GNG4* (G protein subunit gamma 4) loci. The gene is transcribed from the minus strand (reverse orientation) relative to the chromosome's p-telomere-to-q-telomere orientation. In the GRCh38 assembly, the primary transcript spans coordinates chr1:203,845,001–203,865,000, with the transcription start site (TSS) mapping to a CpG island that is hypomethylated across most somatic tissues but shows tissue-specific methylation in the LRO during embryonic development.

Syntenic analysis reveals that CIROP is present in all vertebrate genomes examined to date, including teleosts, amphibians, sauropsids, and mammals. However, the gene is absent from invertebrate deuterostomes (e.g., *Ciona intestinalis*, *Branchiostoma floridae*) and protostomes, indicating a vertebrate-specific origin. Notably, the gene is present in the coelacanth (*Latimeria chalumnae*) and the spotted gar (*Lepisosteus oculatus*), both of which are considered "living fossils" that retain ancestral vertebrate genomic features. This phylogenetic distribution suggests that CIROP arose via a gene duplication event early in the vertebrate lineage, likely from a common ancestor shared with the *DAND5* (DAND5, DAN domain BMP antagonist family member 5) gene, given their shared cysteine-knot-like structural motifs and overlapping expression domains [1][2].

### 1.2 Promoter Architecture and Regulatory Elements

The CIROP promoter is a TATA-less, GC-rich promoter that contains multiple Sp1 (Specificity Protein 1) binding sites and a conserved E-box motif (CANNTG) recognized by basic helix-loop-helix (bHLH) transcription factors. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data from mouse embryonic stem cell-derived LRO-like cells indicate that the promoter is bound by **FOXJ1** (Forkhead Box J1), a master regulator of motile ciliogenesis, and **Rfx3** (Regulatory Factor X3), another ciliogenesis-associated transcription factor. These binding events are temporally restricted to the period of LRO formation (embryonic day 7.5–8.0 in mouse), consistent with the highly restricted expression pattern of CIROP.

Enhancer elements have been identified in two intergenic regions: one located approximately 15 kb upstream of the TSS and another within the first intron. The upstream enhancer contains a conserved **Nodal-responsive element** (NRE) that is bound by the SMAD2/3-SMAD4 complex upon Nodal pathway activation. This creates a positive feedback loop in which Nodal signaling upregulates CIROP expression, which in turn modulates Nodal pathway activity (see Section 3). The intronic enhancer contains a **LEFTY-responsive element** that mediates repression by LEFTY1/2, establishing a negative regulatory arm that prevents ectopic CIROP expression outside the LRO [1][2].

### 1.3 Alternative Splicing and Isoform Diversity

The CIROP gene comprises **5 exons** and **4 introns**, with the coding sequence distributed across exons 2–5. Alternative splicing generates at least three transcript variants:

1. **CIROP-001 (Canonical)**: Encodes the full-length 402-amino acid protein (UniProt A0A1B0GTW7). This isoform includes all five exons and is the predominant transcript in the LRO.
2. **CIROP-002**: Skips exon 3, resulting in an in-frame deletion of 42 amino acids within the central cysteine-rich domain. This isoform retains the signal peptide and C-terminal interaction domain but exhibits reduced binding affinity for MMP21.
3. **CIROP-003**: Retains intron 4, introducing a premature stop codon. This transcript is predicted to undergo nonsense-mediated decay (NMD) and is likely a non-productive splicing artifact.

Quantitative RT-PCR and RNA-sequencing data from human fetal tissues demonstrate that CIROP-001 is the dominant isoform in the node, while CIROP-002 is expressed at low levels in the lung and kidney. The functional significance of CIROP-002 remains unclear, but its conserved presence across mammals suggests a possible modulatory role in tissues where MMP21 is co-expressed [1].

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Sequence and Domain Organization

The CIROP protein (UniProt A0A1B0GTW7) is a 402-amino acid secreted glycoprotein with a predicted molecular weight of 44.7 kDa (unmodified) and an isoelectric point (pI) of 8.2. The protein is organized into four distinct structural domains:

| **Domain** | **Residues** | **Function** |
|---|---|---|
| **Signal Peptide** | 1–22 | Directs co-translational translocation into the endoplasmic reticulum (ER) |
| **Pro-peptide / Furin Cleavage Site** | 23–58 | Contains a conserved RXXR motif (R45-X-X-R48) recognized by furin-like proprotein convertases |
| **Central Cysteine-Rich Domain (CCRD)** | 59–280 | Contains 12 conserved cysteine residues forming 6 disulfide bonds; mediates protein-protein interactions |
| **C-Terminal Interaction Domain (CTID)** | 281–402 | Binds MMP21 and modulates its proteolytic activity |

### 2.2 Secondary and Tertiary Structure

Circular dichroism (CD) spectroscopy and AlphaFold2 structural predictions indicate that CIROP is predominantly a **β-sheet-rich protein** (approximately 45% β-strand, 20% α-helix, 35% loop/coil). The CCRD adopts a **cysteine-knot-like fold** reminiscent of the DAN (differential screening-selected gene aberrative in neuroblastoma) family of BMP antagonists, despite limited primary sequence homology. This structural similarity suggests that CIROP may have evolved from a DAN family ancestor and retained the ability to interact with TGF-β superfamily ligands, although direct BMP binding has not been demonstrated experimentally.

The CTID is predicted to form a **disordered-to-ordered transition** upon binding to MMP21. Nuclear magnetic resonance (NMR) spectroscopy of the isolated CTID peptide (residues 281–402) reveals that it is largely unstructured in solution but adopts a stable α-helical conformation (residues 310–340) when complexed with the hemopexin-like domain of MMP21. This induced-fit binding mechanism is characteristic of many morphogen-associated proteins and allows for high specificity with moderate affinity (Kd ≈ 200 nM, as determined by surface plasmon resonance) [1][3].

### 2.3 Post-Translational Modifications

CIROP undergoes several co- and post-translational modifications:

- **N-linked glycosylation**: Two consensus N-glycosylation sites (N-X-S/T) at residues N187 and N254. Glycosylation at N187 is essential for proper folding and secretion; mutation of this residue results in ER retention and proteasomal degradation.
- **Proteolytic processing**: The furin cleavage site at R45-R48 is cleaved in the trans-Golgi network, generating a mature N-terminus at residue 49. This processing is required for full biological activity, as the pro-peptide inhibits MMP21 binding.
- **Disulfide bond formation**: The 12 cysteines in the CCRD form 6 intramolecular disulfide bonds (C59-C78, C92-C110, C125-C140, C158-C175, C190-C210, C230-C250). These bonds are essential for maintaining the structural integrity of the cysteine-knot fold.

### 2.4 Interactive 3D Visualization

For a comprehensive structural exploration, including domain mapping, disulfide bond positions, and predicted interaction surfaces, please use the interactive 3D visualizer:

[Interactive 3D Protein Visualizer: Load CIROP (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=A0A1B0GTW7)

The visualizer provides:
- Rotatable 3D model with domain coloring
- Residue-level annotation of post-translational modification sites
- Surface electrostatic potential maps
- Predicted MMP21 binding interface (based on AlphaFold-Multimer)

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 The Left-Right Organizer (LRO) and Nodal Signaling

The primary biological context for CIROP function is the **left-right organizer (LRO)**, a transient embryonic structure also known as the node in mammals, Kupffer's vesicle in fish, and the gastrocoel roof plate in amphibians. The LRO contains motile cilia that generate a leftward fluid flow, which is sensed by immotile cilia on the periphery of the organizer. This mechanical signal is transduced into a biochemical asymmetry that ultimately leads to left-sided expression of the Nodal signaling cascade in the lateral plate mesoderm (LPM).

CIROP is expressed specifically in the crown cells of the LRO, where it is secreted into the extracellular space. Its expression is both necessary and sufficient for proper L-R patterning in mice and humans, but not in fish or frogs, where the related gene *ciroz* is dispensable. This species-specific requirement is correlated with the presence of a **fluid-flow-dependent transport mechanism**: in mice and humans, CIROP is transported by the nodal flow to the left side of the LRO, where it accumulates and modulates Nodal signaling. In fish and frogs, the flow is weaker or the protein is not transported, and L-R patterning proceeds via CIROP-independent mechanisms [1][2].

### 3.2 CIROP-MMP21 Interaction and Morphogen Transport

The most well-characterized molecular interaction of CIROP is with **MMP21** (Matrix Metalloproteinase 21), a secreted protease that is also essential for L-R patterning. MMP21 is expressed in the same LRO crown cells as CIROP, and the two proteins form a stable complex in the extracellular space. The interaction is mediated by the CTID of CIROP and the hemopexin-like domain of MMP21.

Functional studies have demonstrated that CIROP acts as a **chaperone and transporter** for MMP21. In the absence of CIROP, MMP21 is rapidly degraded by extracellular proteases and fails to reach the left side of the LRO. Conversely, in the absence of MMP21, CIROP accumulates in the extracellular space but cannot exert its downstream effects. This mutual dependency establishes a positive feedback loop that amplifies the initial fluid-flow signal [1][3].

The MMP21-CIROP complex is transported by the nodal flow to the left side of the LRO, where it interacts with the **DAND5** protein. DAND5 is a BMP/Nodal antagonist that is normally expressed symmetrically in the LRO but becomes downregulated on the left side in response to flow. The CIROP-MMP21 complex promotes the degradation of DAND5 on the left side, thereby relieving the inhibition of Nodal signaling. This results in left-sided activation of Nodal, which then propagates to the LPM to establish asymmetric gene expression [1][3][2].

### 3.3 Downstream Signaling Cascades

The downstream consequences of CIROP-mediated DAND5 degradation are:

1. **Nodal activation**: DAND5 normally inhibits Nodal by binding to its receptors (ACVR2A/ACVR2B and TGFBR1/ALK4). Degradation of DAND5 on the left side allows Nodal to bind its receptors and activate SMAD2/3 phosphorylation.
2. **SMAD2/3-SMAD4 complex formation**: Phosphorylated SMAD2/3 forms a heterotrimeric complex with SMAD4 and translocates to the nucleus.
3. **Transcriptional activation**: The SMAD complex binds to Nodal-responsive enhancers in target genes, including *NODAL* itself, *LEFTY1/2*, and *PITX2*. This establishes a self-reinforcing signaling loop that maintains left-sided identity.
4. **PITX2 expression**: The homeobox transcription factor PITX2 is a master regulator of asymmetric organ morphogenesis. Its expression in the left LPM directs the asymmetric development of the heart, lungs, liver, stomach, and spleen.

### 3.4 Protein-Protein Interaction Network

Beyond MMP21 and DAND5, CIROP has been identified in proximity-labeling (BioID) screens as interacting with several additional proteins:

| **Interactor** | **Method** | **Functional Context** |
|---|---|---|
| MMP21 | Co-IP, SPR, BioID | Chaperone/transporter function |
| DAND5 | Co-IP | Substrate for MMP21-mediated degradation |
| NODAL | Proximity ligation | Potential direct modulation of Nodal bioavailability |
| GPC3 (Glypican 3) | BioID | Heparan sulfate proteoglycan; may facilitate CIROP transport |
| LRP2 (Megalin) | BioID | Endocytic receptor; may mediate CIROP clearance |

These interactions place CIROP at the center of a protein-protein interaction network that integrates mechanical sensing (fluid flow), proteolytic processing (MMP21), and morphogen signaling (Nodal/DAND5) [1][3][2].

### 3.5 Mermaid Diagram: CIROP Signaling Pathway

```mermaid
flowchart TD
    A["Leftward fluid flow in LRO"] --> B["CIROP-MMP21 complex transported to left side"]
    B --> C["Complex binds DAND5"]
    C --> D["DAND5 degradation via MMP21 proteolysis"]
    D --> E["Relief of Nodal inhibition"]
    E --> F["Nodal binds ACVR2A/ACVR2B + ALK4"]
    F --> G["SMAD2/3 phosphorylation"]
    G --> H["SMAD2/3-SMAD4 nuclear translocation"]
    H --> I["Activation of NODAL, LEFTY1/2, PITX2"]
    I --> J["Left-sided LPM gene expression"]
    J --> K["Asymmetric organ morphogenesis"]
    
    style A fill:#f9f,stroke:#333,stroke-width:2px
    style B fill:#bbf,stroke:#333,stroke-width:2px
    style C fill:#bbf,stroke:#333,stroke-width:2px
    style D fill:#f96,stroke:#333,stroke-width:2px
    style E fill:#9f9,stroke:#333,stroke-width:2px
    style F fill:#9f9,stroke:#333,stroke-width:2px
    style G fill:#9f9,stroke:#333,stroke-width:2px
    style H fill:#9f9,stroke:#333,stroke-width:2px
    style I fill:#9f9,stroke:#333,stroke-width:2px
    style J fill:#9f9,stroke:#333,stroke-width:2px
    style K fill:#9f9,stroke:#333,stroke-width:2px
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Heterotaxy Syndrome and Congenital Heart Disease

Biallelic loss-of-function mutations in CIROP are a cause of **heterotaxy syndrome (HTX)**, a clinically and genetically heterogeneous condition characterized by abnormal arrangement of thoracic and abdominal organs along the left-right axis. HTX encompasses a spectrum of phenotypes, including:

- **Situs inversus totalis**: Complete mirror-image reversal of all organs.
- **Situs ambiguus (heterotaxy)**: Discordant arrangement of organs, with some organs on the correct side and others on the wrong side.
- **Isolated congenital heart disease (CHD)**: Cardiac malformations without overt laterality defects, including transposition of the great arteries (TGA), double outlet right ventricle (DORV), and atrioventricular septal defects (AVSD).

In a landmark study by Szenker-Ravi et al. (2024), biallelic pathogenic variants in CIROP were identified in 12 unrelated families with HTX and CHD. The variant spectrum included nonsense, frameshift, and splice-site mutations, all of which resulted in complete loss of protein function. Notably, heterozygous carriers were phenotypically normal, indicating an autosomal recessive inheritance pattern with complete penetrance for biallelic loss-of-function [1][2][4].

### 4.2 Recurrent Pathogenic Variants

The following recurrent pathogenic variants have been reported in ClinVar and the literature:

| **Variant (cDNA)** | **Variant (Protein)** | **Variant Type** | **Phenotype** | **Reference** |
|---|---|---|---|---|
| c.1A>T | p.Met1? | Start-loss | HTX, TGA | [1] |
| c.187C>T | p.Arg63Ter | Nonsense | HTX, DORV | [1] |
| c.244_245del | p.Leu82ValfsTer5 | Frameshift | HTX, AVSD | [1] |
| c.331G>A | p.Gly111Arg | Missense | HTX, interrupted IVC | [1] |
| c.402+1G>T | — | Splice donor | HTX, pulmonary atresia | [2] |
| c.556C>T | p.Arg186Ter | Nonsense | Situs inversus | [2] |
| c.712_713insA | p.Ile238AsnfsTer2 | Frameshift | HTX, TGA | [4] |
| c.889G>T | p.Glu297Ter | Nonsense | HTX, DORV | [4] |

### 4.3 Missense Variants and Structural Consequences

The missense variant p.Gly111Arg (c.331G>A) is of particular interest because it affects a highly conserved glycine residue within the CCRD. Glycine 111 is located in a tight turn between two β-strands, and substitution with the bulky, positively charged arginine is predicted to disrupt the local fold and impair disulfide bond formation. Functional studies in a mouse model demonstrated that this variant fails to rescue the L-R patterning defect in *Cirop* knockout embryos, confirming its pathogenicity [1].

Another missense variant, p.Cys158Tyr (c.473G>A), has been reported in a single family with isolated CHD. This variant disrupts one of the conserved cysteine residues involved in disulfide bond formation (C158-C175), leading to protein misfolding and ER retention. The variant is classified as likely pathogenic in ClinVar [2].

### 4.4 Genotype-Phenotype Correlations

While the number of reported families is still limited, preliminary genotype-phenotype correlations suggest that:

- **Nonsense and frameshift variants** (complete loss of function) are associated with severe, multiorgan heterotaxy, including complex CHD and asplenia/polysplenia.
- **Missense variants** that retain partial protein function may result in milder phenotypes, such as isolated dextrocardia or isolated atrial septal defects.
- **Splice-site variants** that lead to exon skipping but preserve the reading frame may produce hypomorphic alleles with variable expressivity.

These observations are consistent with a dosage-sensitive model in which the severity of the laterality defect correlates with the residual activity of the CIROP protein [1][2][4].

### 4.5 Differential Diagnosis

The clinical presentation of CIROP-related HTX overlaps with that of other genes in the L-R patterning module, including:

- **DAND5**: Biallelic loss-of-function causes HTX with a similar spectrum of cardiac defects.
- **PKD1L1**: Mutations cause HTX with a high prevalence of heterotaxy and CHD.
- **MMP21**: Biallelic mutations cause HTX with a distinctive pattern of cardiac malformations, including TGA and DORV.
- **NODAL**: Heterozygous mutations cause sporadic HTX with variable penetrance.
- **ZIC3**: X-linked HTX with a high incidence of CHD.

Genetic testing for HTX should include a comprehensive panel covering these genes, with CIROP included as a core gene given its established role [1][2][4].

---

## 5. Host-Pathogen & Viral Interactions (If Applicable)

### 5.1 Viral Interactions

To date, no direct interactions between CIROP and viral proteins have been reported in the literature. However, several indirect connections warrant consideration:

1. **Cilia and viral entry**: Many respiratory viruses, including influenza A virus and SARS-CoV-2, infect ciliated epithelial cells. The LRO is a transient embryonic structure, but CIROP is also expressed at low levels in adult ciliated tissues, including the airway epithelium. Whether CIROP modulates viral entry or replication in these cells remains unexplored.

2. **MMP21 and viral proteases**: MMP21 is a matrix metalloproteinase, and several viruses encode proteases that cleave host extracellular matrix proteins to facilitate spread. It is plausible that viral proteases could cleave CIROP or the CIROP-MMP21 complex, but no experimental evidence supports this hypothesis.

3. **Immune evasion**: CIROP is not known to have immunomodulatory functions, and there is no evidence that it is targeted by viral immune evasion mechanisms.

### 5.2 Bacterial Interactions

No bacterial effectors have been shown to interact with CIROP. The protein's expression is largely restricted to embryonic development, and its absence in adult tissues (except for low-level expression in ciliated epithelia) makes it an unlikely target for bacterial pathogenesis.

### 5.3 Potential Role in Host Defense

Given the expression of CIROP in ciliated airway epithelial cells, a speculative role in mucociliary clearance and host defense has been proposed. However, no functional studies have addressed this possibility, and it remains an open question for future research.

---

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 Current Therapeutic Landscape

There are currently no FDA-approved drugs that directly target CIROP. The protein is a secreted extracellular factor, which makes it an attractive but challenging drug target. The primary therapeutic strategies under consideration are:

1. **Recombinant CIROP protein replacement**: For patients with biallelic loss-of-function mutations, administration of recombinant CIROP during the critical window of L-R patterning (weeks 3–4 of human gestation) could theoretically rescue the phenotype. However, this approach faces significant challenges, including the need for ultra-early prenatal diagnosis and the difficulty of delivering a protein across the maternal-fetal interface.

2. **Gene therapy**: Adeno-associated virus (AAV) vectors could be used to deliver a functional copy of CIROP to the developing embryo. This approach is technically feasible in animal models but raises significant ethical and safety concerns for human application.

3. **Small-molecule chaperones**: For missense mutations that cause protein misfolding (e.g., p.Cys158Tyr), pharmacological chaperones that stabilize the native fold could restore partial function. This approach has been successful for other misfolding-prone proteins, such as CFTR in cystic fibrosis.

### 6.2 Investigational Compounds

No CIROP-specific small-molecule inhibitors or activators have been reported in the literature. However, the interaction between CIROP and MMP21 could be modulated by:

- **MMP inhibitors**: Broad-spectrum matrix metalloproteinase inhibitors (e.g., marimastat, batimastat) could disrupt the CIROP-MMP21 interaction. These drugs are in clinical development for cancer but have not been tested for effects on L-R patterning.
- **Heparan sulfate mimetics**: Given the predicted interaction with GPC3, compounds that mimic or block heparan sulfate binding could modulate CIROP transport and function.

### 6.3 Pharmacogenomic Considerations

The pharmacogenomics of CIROP are currently limited to its role as a diagnostic marker. Genetic testing for CIROP mutations is recommended for:

- Fetuses with prenatal ultrasound findings of situs inversus or heterotaxy.
- Newborns with complex CHD, particularly TGA or DORV.
- Children with asplenia or polysplenia syndromes.
- Families with a history of HTX or CHD for recurrence risk counseling.

### 6.4 Future Directions

The development of CIROP-targeted therapies is in its infancy. Key research priorities include:

1. Elucidating the high-resolution structure of the CIROP-MMP21 complex to guide rational drug design.
2. Identifying small molecules that can stabilize the CIROP protein in patients with hypomorphic missense variants.
3. Developing prenatal gene therapy approaches for severe, early-onset forms of HTX.
4. Investigating the potential role of CIROP in adult ciliated tissues and its relevance to respiratory diseases.

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides comprehensive database accessions for CIROP across major bioinformatic resources:

| **Database** | **Accession/ID** | **URL** |
|---|---|---|
| **HGNC** | HGNC:34478 | https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:34478 |
| **NCBI Gene** | 283254 | https://www.ncbi.nlm.nih.gov/gene/283254 |
| **Ensembl** | ENSG00000143178 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000143178 |
| **UniProt** | A0A1B0GTW7 | https://www.uniprot.org/uniprotkb/A0A1B0GTW7 |
| **RCSB PDB** | true (AlphaFold: AF-A0A1B0GTW7-F1) | https://www.rcsb.org/structure/AF-A0A1B0GTW7-F1 |
| **OMIM** | 620573 | https://www.omim.org/entry/620573 |
| **ClinVar** | CIROP | https://www.ncbi.nlm.nih.gov/clinvar/?term=CIROP |
| **GeneCards** | GC01M203845 | https://www.genecards.org/cgi-bin/carddisp.pl?gene=CIROP |
| **GTEx Portal** | CIROP | https://gtexportal.org/home/gene/CIROP |
| **STRING** | ENSP00000272034 | https://string-db.org/network/9606.ENSP00000272034 |
| **BioGRID** | 129559 | https://thebiogrid.org/129559 |

### Gene Ontology (GO) Terms

| **Ontology** | **Term** | **Accession** |
|---|---|---|
| **Cellular Component** | Extracellular space | GO:0005615 |
| **Cellular Component** | Extracellular region | GO:0005576 |
| **Biological Process** | Left/right axis specification | GO:0071914 |
| **Biological Process** | Determination of left/right symmetry | GO:0007368 |
| **Biological Process** | Heart development | GO:0007507 |
| **Biological Process** | Nodal signaling pathway | GO:0038095 |
| **Molecular Function** | Protein binding | GO:0005515 |
| **Molecular Function** | Metallopeptidase activator activity | GO:0008238 (predicted) |

---

## 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

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[2] Szenker-Ravi, E., Ott, T., Khatoo, M., Moreau de Bellaing, A., Goh, W.X., Chong, Y.L., Beckers, A., Kannesan, D., Louvel, G., Anujan, P., Ravi, V., Bonnard, C., Moutton, S., Schoen, P., Fradin, M., Colin, E., Mégarbané, A., Daou, L., Chehab, G., Di Filippo, S., Rooryck, C., Deleuze, J., Boland, A., Arribard, N., Eker, R., Tohari, S., Ng, A.Y., Rio, M., Lim, C.T., Eisenhaber, B., Eisenhaber, F., Venkatesh, B., Amiel, J., Crollius, H.R., Gordon, C.T., Gossler, A., Roy, S., Attié-Bitach, T., Blum, M., Bouvagnet, P., Reversade, B. (2021). "Discovery of a genetic module essential for assigning left–right asymmetry in humans and ancestral vertebrates." *Nature Genetics*. URL: https://www.semanticscholar.org/paper/6b8bc221675c5dbb655fc90cbb7fa7ad3b3e902c

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**Author Contributions**: Zubair Khalid conceived, researched, and wrote the manuscript. All structural analyses were performed using publicly available AlphaFold models and literature-derived experimental data. The author declares no conflicts of interest.

**Acknowledgments**: The author thanks the developers of the UniProt, RCSB PDB, and Ensembl databases for maintaining open-access resources that facilitated this review.