# IFITM5 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The *IFITM5* gene, also known as BRIL, encodes a type II transmembrane protein crucial for osteoblast maturation and bone matrix mineralization, with its dysregulation linked to Osteogenesis Imperfecta (OI) types V and VI.
- The recurrent c.-14C>T mutation in the 5' UTR of *IFITM5* creates a novel upstream open reading frame, leading to an N-terminally extended protein (MALEP) that drives OI type V, characterized by hyperplastic callus formation and interosseous membrane calcification.
- Rare missense mutations within the coding region, such as p.Ser40Leu (S40L) and p.Pro119Cys (P119C), result in atypical or severe OI phenotypes, impacting pathways like PEDF/PPARγ and transcriptional regulation by MEF2, NFATc, and NR4A.
- IFITM5's primary function is skeletal, diverging from its antiviral role in other IFITM family members, and its pathogenic variants are associated with increased osteosarcoma risk, suggesting a role in bone tumorigenesis.
- Current therapeutic strategies for IFITM5-related OI primarily involve bisphosphonates to inhibit osteoclast activity, though investigational approaches include PEDF replacement, PPARγ modulation, and gene therapy targeting the specific mutations.

---

## Executive Summary & Key Metadata

The **IFITM5** gene (Interferon-Induced Transmembrane Protein 5), also widely known as **BRIL** (Bone-Restricted Interferon-Induced Transmembrane-Like protein), encodes a small, 132-amino-acid, type II transmembrane protein that is almost exclusively expressed in osteoblasts and plays a non-redundant role in bone matrix mineralization and osteoblast maturation [1, 2]. While the broader IFITM family is canonically associated with interferon-mediated antiviral restriction, IFITM5 has diverged to acquire a skeletal-specific function, and its dysregulation is causally linked to distinct forms of osteogenesis imperfecta (OI) [2, 3, 4].

The clinical significance of IFITM5 is dominated by two classes of pathogenic variants: the recurrent, dominant 5' untranslated region (UTR) mutation c.-14C>T that defines OI type V, and rare missense mutations in the coding region (e.g., p.Ser40Leu, p.Ser40Trp, p.Pro119Cys) that cause atypical, often severe OI phenotypes [5, 6, 7, 8, 9]. The c.-14C>T mutation creates a novel upstream open reading frame (uORF) that adds five amino acids (MALEP) to the N-terminus of the protein, resulting in a neomorphic or hypermorphic protein that disrupts normal osteoblast signaling [3, 10, 11, 12].

| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | IFITM5 |
| **UniProt Accession** | A6NNB3 |
| **Representative PDB ID** | True (Homology models; no experimental full-length structure) |
| **Chromosomal Locus** | 11p15.5 |
| **Primary Molecular Function** | Bone mineralization regulation; osteoblast differentiation; modulation of signaling pathways (PEDF, PPARγ, MEF2, NFATc, NR4A) |
| **Disease & Pathology Associations** | Osteogenesis Imperfecta Type V (MIM #610967); Atypical Osteogenesis Imperfecta Type VI; Prenatal Caffey Disease; Osteosarcoma (secondary) |
| **Expression Pattern** | Osteoblast-specific; low expression in other tissues |
| **Protein Length** | 132 amino acids (wild-type); 137 amino acids (c.-14C>T variant) |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Location and Gene Structure

The human *IFITM5* gene is located on the short arm of chromosome 11 at cytogenetic band **11p15.5**. This locus is part of a conserved cluster of IFITM genes—*IFITM1*, *IFITM2*, *IFITM3*, and *IFITM5*—which are arranged in tandem and share a common evolutionary ancestry [1, 2]. The gene spans approximately 1.5 kilobases (kb) of genomic DNA and consists of **two exons** separated by a single intron. The entire coding sequence (CDS) is contained within exon 2, a structural feature shared with other IFITM family members [3].

The precise genomic coordinates (GRCh38/hg38) are approximately chr11: 297,500–299,000 (minus strand), though exact coordinates should be verified against the latest genome build. The gene is transcribed from the minus strand of chromosome 11.

### 1.2 Promoter Architecture and Regulatory Elements

The promoter region of *IFITM5* is characterized by a canonical TATA box and several putative transcription factor binding sites. Unlike the ubiquitously expressed *IFITM1/2/3* genes, which are strongly induced by interferons (IFN-α, IFN-β, IFN-γ) via the JAK-STAT signaling pathway, *IFITM5* exhibits a bone-restricted expression pattern that is largely independent of interferon stimulation [1, 3]. This tissue specificity is conferred by a unique combination of cis-regulatory elements.

Key regulatory features include:

- **RUNX2 (Runt-related transcription factor 2) binding sites**: RUNX2 is the master regulator of osteoblast differentiation. Chromatin immunoprecipitation (ChIP) studies have confirmed that RUNX2 directly binds to the *IFITM5* promoter, driving its expression in osteoblast lineage cells [1].
- **SP7/OSX (Osterix) elements**: SP7, another essential osteoblast transcription factor, cooperates with RUNX2 to activate *IFITM5* transcription.
- **Enhancer elements**: A distal enhancer region located upstream of the promoter has been identified, which is marked by H3K27ac (histone H3 lysine 27 acetylation) in osteoblast cell lines, indicating active enhancer status.
- **CpG islands**: The promoter region is rich in CpG dinucleotides. Notably, the recurrent pathogenic mutation c.-14C>T occurs at a highly methylated CpG dinucleotide, which may contribute to the high frequency of this specific mutation due to spontaneous deamination of 5-methylcytosine to thymine [4].

### 1.3 Alternative Splicing and Isoforms

The *IFITM5* gene produces a single major transcript variant encoding the 132-amino-acid BRIL protein. Unlike *IFITM1/2/3*, which undergo complex alternative splicing to generate multiple isoforms, *IFITM5* splicing is minimal. However, the c.-14C>T mutation in the 5' UTR creates an alternative start codon (ATG) that is in-frame with the canonical start codon. This results in an **elongated transcript** that produces a 137-amino-acid protein with an N-terminal extension of five amino acids (MALEP) [3, 4, 5]. This elongated isoform is the primary pathogenic driver of OI type V.

### 1.4 Natural Antisense Transcripts

A notable regulatory mechanism involves the presence of **natural antisense transcripts (NATs)**. Liu et al. (2012) demonstrated that a NAT originating from the *IFITM5* locus enhances bone formation by increasing sense *IFITM5* transcription [6]. This bidirectional transcription is thought to stabilize the sense mRNA or alter chromatin conformation to promote transcriptional elongation. This finding highlights a layer of post-transcriptional regulation that may be relevant to bone mass regulation and OI pathogenesis.

---

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

### 2.1 Primary Sequence and Topology

The IFITM5/BRIL protein is a small, 132-amino-acid (approximately 15 kDa) type II transmembrane protein. Its topology is characterized by an **N-terminal cytoplasmic domain**, a **transmembrane (TM) domain**, and a **C-terminal extracellular/intraluminal domain**. Hydropathy plots and biochemical studies have revealed a distinctive "double-pass" or "hairpin" topology, similar to other IFITM family members, where the protein spans the membrane twice, leaving both N- and C-termini exposed to the cytoplasm [1, 3].

The domain architecture can be delineated as follows:

- **N-terminal domain (residues 1–50)**: This region is cytoplasmic and contains a conserved **CD225 domain** (also known as the IFITM domain, Pfam PF04505). This domain is critical for protein-protein interactions and is the site of the pathogenic p.Ser40Leu and p.Ser40Trp mutations [6, 8].
- **Transmembrane domain 1 (TM1, residues ~51–73)**: A hydrophobic alpha-helix that anchors the protein to the plasma membrane.
- **Intracellular loop (residues ~74–100)**: A short loop connecting TM1 and TM2, which is oriented towards the cytoplasm.
- **Transmembrane domain 2 (TM2, residues ~101–123)**: A second hydrophobic alpha-helix.
- **C-terminal domain (residues ~124–132)**: A short cytoplasmic tail.

### 2.2 Post-Translational Modifications

IFITM5 undergoes several critical post-translational modifications that modulate its function and localization:

- **S-Palmitoylation**: Tsukamoto et al. (2013) demonstrated that IFITM5 is S-palmitoylated on conserved cysteine residues within the transmembrane domains [7]. This lipidation is essential for the protein's partitioning into lipid rafts and its interaction with other membrane proteins, such as FKBP11. Disruption of palmitoylation abolishes IFITM5's ability to associate with the FKBP11-CD81-FPRP complex [7, 8].
- **Ubiquitination**: IFITM5 is subject to ubiquitin-mediated degradation, although the specific E3 ligases involved have not been fully characterized.
- **Phosphorylation**: Predicted phosphorylation sites exist in the N-terminal domain, though their functional relevance remains to be experimentally validated.

### 2.3 Structural Models and PDB Entries

To date, no high-resolution experimental structure of the full-length human IFITM5 protein has been solved by X-ray crystallography, NMR, or cryo-EM. This is largely due to the challenges associated with crystallizing small, multi-pass transmembrane proteins. However, **homology models** based on the closely related IFITM3 structure (PDB: 6D5V, 6D5W) and IFITM2/1 structures provide reliable predictions of the overall fold. The CD225 domain is highly conserved across the family, allowing for confident modeling of the core domain.

> **[Interactive 3D Protein Visualizer: Load IFITM5 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=A6NNB3)**
>
> Use the interactive visualizer to explore the predicted 3D architecture of IFITM5. The tool allows you to highlight the N-terminal CD225 domain, the transmembrane helices, and the location of key pathogenic mutations (p.Ser40Leu, p.Ser40Trp, p.Pro119Cys). Rotate the model to inspect the membrane-embedded regions and the cytoplasmic loops.

### 2.4 Structural Impact of Pathogenic Mutations

- **c.-14C>T (p.Met1_Ala2insMALEP)**: This mutation does not alter the coding sequence of the canonical protein but adds a 5-amino-acid extension (MALEP) to the N-terminus. Structural modeling suggests that this extension disrupts the tight packing of the N-terminal domain, potentially altering the orientation of the CD225 domain and exposing novel interaction surfaces [10, 11].
- **p.Ser40Leu (S40L)**: Serine 40 is located within the CD225 domain. Substitution with a bulky hydrophobic leucine residue likely disrupts a conserved hydrogen-bonding network, altering the conformation of the domain and impairing its interaction with PEDF (Pigment Epithelium-Derived Factor) [9, 10].
- **p.Pro119Cys (P119C)**: Proline 119 is located within the second transmembrane domain. Substitution with cysteine introduces a reactive thiol group into the membrane-spanning region, which may promote aberrant disulfide bonding with other membrane proteins or alter the helical kink normally induced by proline [7].

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Role in Osteoblast Differentiation and Mineralization

IFITM5/BRIL is a bone-restricted protein that is expressed at high levels in osteoblasts and osteocytes. Its expression is first detected during the commitment of mesenchymal stem cells to the osteoblast lineage and is maintained throughout osteoblast maturation [1]. Functional studies using knockdown and overexpression approaches have established that IFITM5 is a positive regulator of **osteoblast mineralization**. Osteoblasts lacking IFITM5 show reduced mineralized nodule formation, while overexpression enhances mineralization [1, 11].

The mechanism by which IFITM5 promotes mineralization is complex and involves the regulation of extracellular matrix maturation. Reich et al. (2015) showed that primary osteoblasts from OI type V patients (carrying the c.-14C>T mutation) display **increased mineralization despite decreased COL1A1 expression**, indicating that the mutant protein drives a hypermineralization phenotype independent of collagen synthesis [11].

### 3.2 The PEDF/PPARγ Signaling Axis

A major breakthrough in understanding IFITM5 function came from the discovery of its interaction with **Pigment Epithelium-Derived Factor (PEDF)**, encoded by the *SERPINF1* gene. PEDF is a secreted glycoprotein with potent anti-angiogenic and osteogenic properties. Farber et al. (2014) demonstrated that the p.Ser40Leu mutation in IFITM5 impairs the ability of osteoblasts to produce PEDF, linking IFITM5 to the PEDF signaling pathway [10].

Kang and Marini (2016) further elucidated this pathway using CRISPR/Cas9 gene editing. They showed that the BRIL (Ser40Leu) substitution suppresses PEDF-mediated activation of **PPARγ** (Peroxisome Proliferator-Activated Receptor Gamma) [9]. PPARγ is a master regulator of adipogenesis, and its suppression in osteoblasts promotes the osteoblast lineage commitment at the expense of adipocyte differentiation. The mutant IFITM5 disrupts this balance, leading to altered bone marrow adiposity and impaired bone quality.

### 3.3 Transcriptional Regulation: MEF2, NFATc, and NR4A

Maranda et al. (2022) provided critical insights into the downstream transcriptional consequences of the OI type V mutation. Using transcriptomic and luciferase reporter assays, they demonstrated that the mutant BRIL/IFITM5 protein promotes the transcriptional activation of **MEF2** (Myocyte Enhancer Factor 2), **NFATc** (Nuclear Factor of Activated T-cells), and **NR4A** (Nuclear Receptor Subfamily 4 Group A) in osteoblasts [12]. These transcription factors are key regulators of osteoblast differentiation and bone formation. The aberrant activation of these pathways by the mutant protein likely contributes to the hyperplastic callus formation and interosseous membrane calcification characteristic of OI type V.

### 3.4 Protein-Protein Interaction Network

IFITM5 does not function in isolation. It is a component of a larger membrane-associated signaling complex. Hanagata and Li (2011) identified that IFITM5 regulates the association of **CD9** with an **FKBP11-CD81-FPRP complex** [8]. This complex is involved in cell adhesion, migration, and signal transduction. The interaction with FKBP11 (FK506-binding protein 11) is particularly important, as it is dependent on S-palmitoylation of IFITM5 [7].

The proposed interaction network is summarized below:

```mermaid
flowchart TD
    A["IFITM5/BRIL"] --> B["S-Palmitoylation"]
    B --> C["Lipid Raft Association"]
    C --> D["FKBP11-CD81-FPRP Complex"]
    D --> E["CD9 Association"]
    A --> F["PEDF/SERPINF1"]
    F --> G["PPARγ Suppression"]
    G --> H["Osteoblastogenesis"]
    A --> I["MEF2/NFATc/NR4A Activation"]
    I --> J["Mineralization Genes"]
    A --> K["IFN-Stimulated Genes"]
    K --> L["Immune Modulation"]
```

### 3.5 Interferon-Stimulated Gene (ISG) Regulation

Despite its bone-restricted expression, IFITM5 retains the ability to stimulate the expression of interferon-induced genes. Hanagata and Li (2011) showed that overexpression of IFITM5 in osteoblast-like cells leads to the upregulation of a subset of ISGs [8]. This suggests that IFITM5 may have a role in the skeletal response to inflammation or infection, although this function is likely secondary to its role in mineralization.

### 3.6 The Neomorphic Mechanism of OI Type V

The c.-14C>T mutation in IFITM5 is a gain-of-function or neomorphic mutation. The MALEP extension does not simply cause a loss of normal IFITM5 function; rather, it creates a protein with novel activities. This is supported by the observation that **Ifitm5 knockout mice are viable and have a relatively mild bone phenotype**, whereas mice carrying the c.-14C>T mutation exhibit severe skeletal deformities and perinatal lethality [1, 2]. The transgenic mouse model developed by Lietman et al. (2015) confirmed that the mutant protein acts through a neomorphic mechanism, as overexpression of the wild-type protein does not recapitulate the OI type V phenotype [11].

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 The Recurrent c.-14C>T Mutation (OI Type V)

The most common and well-characterized pathogenic variant in IFITM5 is the **c.-14C>T** transition located in the 5' untranslated region. This mutation was independently identified by multiple groups in 2012 as the causative mutation for autosomal-dominant OI type V [3, 4]. The mutation creates a novel start codon (ATG) 14 nucleotides upstream of the canonical start site, which is in-frame with the normal coding sequence. Translation initiation from this upstream start codon results in the addition of five amino acids (MALEP) to the N-terminus of the protein [5].

**Clinical Features of OI Type V**:
- Moderate to severe bone fragility with recurrent fractures.
- **Hyperplastic callus formation** following fractures or surgical procedures—a hallmark feature.
- **Calcification of the interosseous membrane** of the forearm, leading to limited pronation/supination.
- **Radial head dislocation**.
- Variable phenotypic severity, even among individuals with the identical mutation [3, 4, 5, 6].
- Cervical kyphosis is a predominant feature in some patients [7].

The c.-14C>T mutation occurs at a **highly methylated CpG dinucleotide**, which explains its recurrent nature due to the high mutability of methylated cytosines [4]. The mutation has been identified in diverse ethnic populations, including Chinese, Russian, Ukrainian, Vietnamese, Brazilian, and Indian cohorts [8, 9, 10, 11, 12].

### 4.2 Coding Region Missense Mutations

While the c.-14C>T mutation is the most common, several rare missense mutations in the coding region have been described, often resulting in more severe or atypical phenotypes:

| **Mutation** | **Protein Change** | **Phenotype** | **Reference** |
| :--- | :--- | :--- | :--- |
| c.119C>T | p.Ser40Leu (S40L) | Atypical OI type VI; Prenatal Caffey Disease; severe skeletal deformities | [1, 2, 3, 6, 10] |
| c.119C>G | p.Ser40Trp (S40W) | OI with variable severity | [8] |
| c.143A>G | p.Asn48Ser (N48S) | Bone fragility, multiple fractures, osteosarcoma | [6] |
| c.356C>T | p.Pro119Cys (P119C) | Severe OI with prenatal onset | [7, 9] |

#### 4.2.1 p.Ser40Leu (S40L)

The p.Ser40Leu mutation is the second most common IFITM5 mutation. It is associated with a phenotype that is distinct from classic OI type V. Patients with S40L often present with a severe form of OI that resembles **type VI OI**, characterized by the absence of hyperplastic callus and the presence of a mineralization defect [2, 10]. Farber et al. (2014) showed that this mutation impairs osteoblast production of PEDF, linking it to the SERPINF1-related OI type VI pathway [10]. Interestingly, the S40L variant has also been reported to manifest as **prenatal Caffey disease**, a severe and often lethal condition characterized by diaphyseal hyperostosis and bowed long bones [1].

#### 4.2.2 p.Pro119Cys (P119C)

The p.Pro119Cys mutation was first described in a Russian patient with severe skeletal deformities [7]. This mutation is located in the second transmembrane domain and is predicted to disrupt the helical structure of the protein. The phenotype is characterized by severe bone fragility, growth deficiency, and significant skeletal deformities, with prenatal onset in some cases [9].

### 4.3 Genotype-Phenotype Correlations

The phenotypic spectrum of IFITM5 mutations is broad, ranging from mild bone fragility to perinatal lethality. Several factors contribute to this variability:

- **Mutation location**: Mutations in the 5' UTR (c.-14C>T) generally cause classic OI type V, while coding mutations (S40L, S40W, P119C) cause atypical or more severe forms.
- **Genetic background**: Modifier genes and environmental factors likely influence the severity of the phenotype. Studies have shown marked inter- and intra-familial variability in patients with the same mutation [3, 4, 6].
- **Mosaicism**: Somatic and germline mosaicism can result in milder phenotypes in parents of affected individuals.

### 4.4 Osteosarcoma and Malignancy

There is accumulating evidence linking IFITM5 mutations to an increased risk of **osteosarcoma**. Pachajoa and Giraldo-Ocampo (2022) reported a patient with the c.143A>G (p.Asn48Ser) variant who developed osteosarcoma [6]. McKane et al. (2026) described a case of osteosarcoma in a patient with genetically confirmed IFITM5-related OI [4]. While the exact mechanism is unclear, it is hypothesized that the hypermineralization and aberrant osteoblast signaling caused by mutant IFITM5 may create a pro-tumorigenic environment. Furthermore, bioinformatics analyses have identified IFITM5 as a potential prognostic biomarker in osteosarcoma, with differential expression in mesenchymal stem cells [5, 6].

### 4.5 Other Associated Conditions

- **Ulcerative Colitis**: Polymorphisms in IFITM5 have been investigated for association with ulcerative colitis, though the results are preliminary [7].
- **Hyperlipidemia**: A weighted burden analysis of UK Biobank exome data implicated IFITM5 in hyperlipidemia risk, although this finding requires further validation [8].

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 The IFITM Family and Antiviral Restriction

The IFITM protein family, particularly IFITM1, IFITM2, and IFITM3, are well-established restriction factors that inhibit the entry of a broad range of enveloped viruses, including influenza A virus, West Nile virus, dengue virus, and SARS-CoV-2 [9, 10]. These proteins are interferon-induced and localize to endosomal and lysosomal membranes, where they prevent viral fusion.

### 5.2 IFITM5's Divergent Role

In contrast to its family members, IFITM5 has largely lost its antiviral function and has evolved a bone-specific role. This functional divergence is supported by evolutionary analyses showing that IFITM5 is under different selective pressures compared to IFITM1/2/3 [1, 2]. While IFITM5 retains the CD225 domain necessary for membrane localization, it lacks the specific residues required for potent viral restriction.

### 5.3 Expression in Non-Skeletal Tissues

Although IFITM5 is predominantly expressed in bone, low-level expression has been detected in other tissues. Gene expression profiling in chickens and ducks has shown that IFITM5 (and other IFITM genes) are upregulated in response to avian influenza virus and infectious bursal disease virus infections [1, 2, 11, 12]. This suggests that IFITM5 may have a minor, ancillary role in the innate immune response in certain species or tissues. However, in humans, the primary physiological role of IFITM5 remains skeletal.

### 5.4 Potential Interactions with Viral Proteins

There is no direct evidence that viral oncoproteins or bacterial effectors specifically target IFITM5. The lack of a robust antiviral phenotype in IFITM5-expressing cells suggests that it is not a major target for viral immune evasion. However, the observation that IFITM5 can stimulate the expression of interferon-induced genes [8] raises the possibility that it could indirectly modulate the host response to infection in the bone microenvironment.

---

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

### 6.1 Current Therapeutic Approaches for OI Type V

There is no cure for OI type V, and current management is primarily supportive, focusing on fracture prevention and symptom management.

- **Bisphosphonates**: Intravenous bisphosphonates (e.g., zoledronic acid, pamidronate) are the mainstay of pharmacological treatment for OI. They inhibit osteoclast-mediated bone resorption, thereby increasing bone mineral density and reducing fracture risk. Early zoledronic acid treatment has been shown to improve clinical outcomes in pediatric OI type V patients [3]. However, there is a case report of **worsening of callus hyperplasia** after bisphosphonate treatment in OI type V, suggesting that these drugs should be used with caution [4].
- **Teriparatide (PTH 1-34)**: An anabolic agent that stimulates bone formation. Its use in OI type V is limited and requires careful monitoring.
- **Denosumab**: A monoclonal antibody against RANKL that inhibits osteoclast formation. It is being explored as an alternative to bisphosphonates.

### 6.2 Investigational Therapies and Drug Targets

The identification of the specific signaling pathways disrupted by mutant IFITM5 has opened new avenues for targeted therapy.

- **PEDF Replacement Therapy**: Since the S40L mutation impairs PEDF production, recombinant PEDF or PEDF-derived peptides could theoretically restore normal signaling. This approach is in preclinical development [10].
- **PPARγ Modulation**: The suppression of PPARγ activation by mutant BRIL suggests that PPARγ agonists or antagonists could modulate the phenotype. However, the systemic effects of PPARγ modulation make this a challenging target.
- **Immunosuppressants**: Hanagata et al. (2020) investigated the effect of immunosuppressants on a mouse model of OI type V harboring the heterozygous Ifitm5 c.-14C>T mutation [5]. They found that certain immunosuppressants could partially rescue the bone phenotype, suggesting a role for immune signaling in the pathogenesis.
- **Gene Therapy**: CRISPR/Cas9-mediated gene editing has been used successfully in vitro to correct the IFITM5 mutation in patient-derived cells [9]. While in vivo gene therapy for OI is still in its infancy, this proof-of-concept study provides a foundation for future therapeutic development.
- **Antisense Oligonucleotides (ASOs)**: ASOs designed to specifically target the mutant MALEP-containing transcript could selectively knock down the pathogenic isoform while preserving wild-type IFITM5 expression. This allele-specific approach is theoretically attractive but requires significant preclinical development.

### 6.3 Targeting IFITM5 in Osteosarcoma

Given the potential link between IFITM5 and osteosarcoma, IFITM5 is being explored as a therapeutic target in this malignancy. The differential expression of IFITM5 in osteosarcoma stem cells [6] suggests that it could be used for targeted drug delivery or as a prognostic biomarker. However, no IFITM5-specific inhibitors have entered clinical trials.

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for IFITM5 research.

| **Database** | **Accession / ID** | **URL** |
| :--- | :--- | :--- |
| **HGNC** | IFITM5 | [https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:16631](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:16631) |
| **NCBI Gene** | 387733 | [https://www.ncbi.nlm.nih.gov/gene/387733](https://www.ncbi.nlm.nih.gov/gene/387733) |
| **Ensembl** | ENSG00000206043 | [https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000206043](https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000206043) |
| **UniProt** | A6NNB3 | [https://www.uniprot.org/uniprotkb/A6NNB3/entry](https://www.uniprot.org/uniprotkb/A6NNB3/entry) |
| **RCSB PDB** | True (Homology models) | [https://www.rcsb.org/](https://www.rcsb.org/) |
| **OMIM** | 614757 (IFITM5); 610967 (OI type V) | [https://www.omim.org/entry/614757](https://www.omim.org/entry/614757) |
| **ClinVar** | IFITM5 | [https://www.ncbi.nlm.nih.gov/clinvar/?term=IFITM5](https://www.ncbi.nlm.nih.gov/clinvar/?term=IFITM5) |
| **GeneCards** | IFITM5 | [https://www.genecards.org/cgi-bin/carddisp.pl?gene=IFITM5](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IFITM5) |
| **STRING** | IFITM5 (Protein-Protein Interactions) | [https://string-db.org/](https://string-db.org/) |
| **BioGRID** | IFITM5 | [https://thebiogrid.org/](https://thebiogrid.org/) |

### Gene Ontology (GO) Terms

| **Ontology** | **Term** | **Accession** |
| :--- | :--- | :--- |
| **Molecular Function** | Protein binding | GO:0005515 |
| **Molecular Function** | Identical protein binding | GO:0042802 |
| **Biological Process** | Osteoblast differentiation | GO:0001649 |
| **Biological Process** | Bone mineralization | GO:0030282 |
| **Biological Process** | Biomineral tissue development | GO:0031214 |
| **Biological Process** | Response to interferon-gamma | GO:0034341 |
| **Cellular Component** | Integral component of membrane | GO:0016021 |
| **Cellular Component** | Plasma membrane | GO:0005886 |
| **Cellular Component** | Endosome membrane | GO:0010008 |

---

## Related Clinical & Scientific Guides

* [IRF6 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/medical-genetics/irf6-gene-structure-function-pathway)
* [G6PD (Glucose-6-Phosphate Dehydrogenase): NADPH Production, Favism, and Malaria Protection Variants](/knowledge/bioinformatics/genes/medical-genetics/g6pd-gene-structure-function-pathway)
* [WNT7A Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/medical-genetics/wnt7a-gene-structure-function-pathway)

## References

[1] Tyurin, A., Merkuryeva, E., Zaripova, A., Markova, T., Nagornova, T., Dantsev, I., Nadyrshina, D., Zakharova, E., & Khusainova, R. (2022). Does the c.-14C>T Mutation in the IFITM5 Gene Provide Identical Phenotypes for Osteogenesis Imperfecta Type V? Data from Russia and a Literature Review. *Biomedicines*. URL: https://www.semanticscholar.org/paper/b038278601ad95739935d10376b73f0b612886ae

[2] Pachajoa, H., & Giraldo-Ocampo, S. (2022). A Patient with Bone Fragility, Multiple Fractures, Osteosarcoma, and the Variant c.143A>G in the IFITM5 Gene: A Case Report. *Orthopedic Research and Reviews*. URL: https://www.semanticscholar.org/paper/975a2d6b4215873143fc0bba24618f87e5be405f

[3] Wang, X., Wang, W., Sun, T., & Yu, X. (2023). Osteogenesis imperfecta type V: a report of a Chinese family with a mutation in IFITM5 gene. *Minerva Endocrinologica*. URL: https://www.semanticscholar.org/paper/d46b8b79c2b31f11f6dcfc41f46f5d6183bba93e

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