FGF3 Gene: Structure, Function, and Clinical Significance

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-08-01

Key Takeaways

• FGF3 is a secreted signaling protein crucial for embryonic development, particularly inner ear, tooth, and hindbrain formation, and its aberrant reactivation via genomic amplification or promoter disruption drives oncogenesis in breast, bladder, esophageal, and head-and-neck squamous cell carcinomas.
• Germline loss-of-function mutations in FGF3 cause LAMM syndrome, an autosomal recessive disorder characterized by labyrinthine aplasia, microtia, and microdontia, with pathogenic variants including missense, nonsense, frameshift, and splice-site mutations.
• The FGF3 gene is located at chromosome 11q13.3 and frequently resides within a co-amplified amplicon in cancers, alongside genes like CCND1 and FGF4, with disruption of surrounding CTCF boundaries also leading to its oncogenic activation.
• FGF3 signals through FGFRs (primarily FGFR1b, FGFR2b) to activate RAS-MAPK, PI3K-AKT, and PLCγ pathways, and therapeutic strategies focus on inhibiting these receptors with selective FGFR inhibitors like erdafitinib and pemigatinib, or using ligand-trapping antibodies.
• The discovery of FGF3 (originally INT-2) as an oncogene activated by Mouse Mammary Tumor Virus (MMTV) insertional mutagenesis in mice highlights a key mechanism of proto-oncogene activation relevant to understanding its role in tumorigenesis.

Executive Summary & Key Metadata

The Fibroblast Growth Factor 3 (FGF3) gene, historically designated as INT-2 (murine mammary tumor virus integration site 2), encodes a secreted signaling protein that belongs to the canonical FGF family. FGF3 is a critical morphogen during embryonic development, particularly for the induction and patterning of the inner ear, tooth development, and hindbrain segmentation. In the adult, FGF3 expression is largely silenced, but its aberrant reactivation through genomic amplification, chromatin boundary disruption, or oncogenic transcription factor mutation contributes to the pathogenesis of multiple solid tumors, including breast, bladder, esophageal, and head-and-neck squamous cell carcinomas. Germline loss-of-function mutations in FGF3 cause the autosomal recessive LAMM syndrome (Labyrinthine Aplasia, Microtia, and Microdontia; OMIM #610706), a rare congenital disorder characterized by profound sensorineural deafness and craniofacial anomalies.

1. Genomic Locus, Chromosomal Organization & Isoforms

1.1 Chromosomal Localization and Gene Structure

The human FGF3 gene is located on the long (q) arm of chromosome 11 at cytogenetic band 11q13.3 (GRCh38/hg38: chr11:69,654,885-69,663,190; ~8.3 kb). This locus is a well-characterized region of genomic instability and amplification in human cancers. The gene is oriented in the minus (reverse) strand direction relative to the centromere-to-telomere orientation of chromosome 11.

The FGF3 gene consists of three exons and two introns, a structure conserved across vertebrate orthologs, including the zebrafish fgf3 gene [1]. The coding sequence spans approximately 2.1 kb, encoding a precursor protein of 239 amino acids (UniProt P11487). The mature, secreted protein is generated after cleavage of a 17-amino-acid N-terminal signal peptide, yielding a ~222-amino-acid mature polypeptide.

1.2 The 11q13 Amplicon and Genomic Context

FGF3 resides within a gene-dense region that is frequently co-amplified in human cancers. The core 11q13 amplicon typically encompasses several oncogenes, including CCND1 (Cyclin D1), FGF4, FGF19, and EMS1 (Cortactin) [2, 3]. The proximity of these genes complicates the attribution of oncogenic phenotypes to a single driver; however, functional studies have demonstrated that FGF3 and FGF4 can act as bonafide oncogenes when overexpressed [4, 5]. The amplicon structure is not monolithic; distinct amplicon cores exist, and FGF3 can be amplified independently of CCND1 in some tumor types, suggesting a selective pressure for FGF3 overexpression [6].

The genomic region surrounding FGF3 is organized into a topologically associating domain (TAD) that is delimited by CCCTC-binding factor (CTCF) boundaries. A specific CTCF boundary located between FGF3 and its neighboring genes acts as an insulator, preventing aberrant enhancer-promoter interactions. Disruption of this boundary, either through somatic mutation, DNA methylation, or deletion of the CTCF motif, leads to the activation of FGF3 and FGF4 oncogenes by distal enhancers [7, 8, 9]. This mechanism is particularly relevant in SDH-deficient GISTs, where genome-wide DNA hypermethylation disrupts CTCF binding, leading to the aberrant expression of FGF3 and FGF4 [10].

1.3 Promoter Architecture and Transcriptional Regulation

The FGF3 promoter lacks a canonical TATA box but contains a GC-rich region with multiple putative Sp1 binding sites. The basal promoter activity is low in most adult tissues, consistent with its tightly regulated developmental expression pattern. Key regulatory elements have been mapped in the mouse Fgf3 ortholog, revealing a complex array of enhancers that drive expression in the hindbrain, otic vesicle, and tooth germ [11].

Transcription factor binding sites:

• Sonic Hedgehog (SHH): The mouse Fgf3 expression in the hindbrain and otic vesicle is dependent on SHH signaling. Genetic ablation of Shh leads to a loss of Fgf3 expression in these domains, indicating a direct or indirect requirement for SHH pathway activity [11].
• KLF4: A specific somatic mutation in the transcription factor KLF4 (K409Q), found in a subset of meningiomas, converts it into a constitutive activator that binds to specific short tandem repeats (STRs) upstream of FGF3, driving its overexpression [12].
• Follistatin/BMP signaling: In the chick hindbrain, FGF3 expression is repressed by Bone Morphogenetic Proteins (BMPs). The BMP inhibitor Follistatin is required to relieve this repression, thereby establishing the segmental expression pattern of FGF3 in rhombomeres [13].

1.4 Alternative Splicing and Isoforms

Unlike many other FGF family members, FGF3 does not undergo extensive alternative splicing to generate functionally distinct protein isoforms. The primary transcript is processed to a single major mRNA species. However, the gene was originally identified as a chimeric transcript (INT-2) in mouse mammary tumors, where it was activated by the insertion of the Mouse Mammary Tumor Virus (MMTV) provirus. This viral insertion resulted in the production of aberrant, truncated transcripts that initiated from viral long terminal repeats (LTRs), leading to constitutive overexpression of the FGF3 coding region.

2. 3D Protein Domain Architecture & Structural Biology

2.1 Primary Sequence and Domain Boundaries

The FGF3 protein (UniProt P11487) is a 239-amino-acid polypeptide with a molecular weight of approximately 26.8 kDa. The domain architecture is typical of the paracrine FGF family:

• Signal Peptide (aa 1-17): Directs the nascent polypeptide to the endoplasmic reticulum (ER) for secretion.
• Heparin-Binding Domain (aa 18-239): The mature protein contains a highly conserved β-trefoil core (approximately aa 30-220), which is the hallmark of all FGFs. This core is composed of 12 antiparallel β-strands arranged into three lobes of four strands each.
• Receptor Binding Sites: The β-trefoil core presents two primary interaction surfaces:
• Primary FGFR binding site: A shallow groove formed by β-strands 10 and 11, which interacts with the immunoglobulin-like domain D2 and the D2-D3 linker of the FGFR.
• Heparin/HS binding site: A positively charged patch on the surface of the protein, composed of basic residues (Lys and Arg), which binds to negatively charged heparan sulfate glycosaminoglycans (HSGAGs). This interaction is required for the formation of a stable FGF-FGFR-HS ternary complex.

2.2 Structural Biology and Homology

While a high-resolution crystal structure of the human FGF3 protein in complex with its receptor has not been solved, the structure is highly homologous to other FGFs, such as FGF1, FGF2, and FGF10, for which crystal structures are available. The core β-trefoil fold is remarkably conserved, with root-mean-square deviation (RMSD) values of less than 1.5 Å across the family. The structural model of FGF3 predicts a canonical fold with a hydrophobic core and surface-exposed residues that dictate its specific receptor-binding affinity.

FGF3 primarily signals through the IIIb splice variants of FGFR1 and FGFR2 (FGFR1b and FGFR2b), which are predominantly expressed on epithelial cells. This is consistent with its role as a mesenchymal or epithelial signaling molecule during development. The specificity for the IIIb isoforms is determined by critical amino acid residues within the β10-β11 loop of FGF3.

2.3 Post-Translational Modifications

• Glycosylation: FGF3 contains a potential N-linked glycosylation site (Asn-X-Ser/Thr) at position Asn-105. Glycosylation is not required for receptor binding but may influence protein stability and secretion efficiency.
• Proteolytic Processing: The signal peptide is cleaved by signal peptidase during ER translocation. There is no evidence for further proteolytic maturation, unlike some other FGFs that can be cleaved to generate shorter isoforms.

Interactive 3D Protein Visualizer Explore the predicted three-dimensional structure of the FGF3 protein, including its β-trefoil core, receptor-binding surfaces, and heparin-binding pocket. Interactive 3D Protein Visualizer: Load FGF3 (PDB: true)

3. Cellular Signaling Pathways & Molecular Function

3.1 The FGF Signaling Cascade

FGF3 functions as a classical paracrine signaling molecule. Upon secretion, it binds to the extracellular domain of its cognate FGFRs (primarily FGFR1b and FGFR2b) on the surface of target cells. This binding is stabilized by the simultaneous interaction of FGF3 and FGFR with heparan sulfate proteoglycans (HSPGs) on the cell surface and in the extracellular matrix. The formation of the FGF3-FGFR-HS ternary complex induces receptor dimerization and trans-autophosphorylation of tyrosine residues within the intracellular kinase domain of the FGFR.

The phosphorylated tyrosines serve as docking sites for adaptor proteins, most notably FRS2α (Fibroblast Growth Factor Receptor Substrate 2α). FRS2α is constitutively associated with the juxtamembrane region of the FGFR. Upon receptor activation, FRS2α is phosphorylated, creating binding sites for the adaptor protein GRB2 and the protein tyrosine phosphatase SHP2. This complex then activates downstream signaling cascades:

1. RAS-MAPK Pathway: GRB2 recruits the guanine nucleotide exchange factor SOS, which activates RAS. RAS triggers the RAF-MEK-ERK kinase cascade. Activated ERK (MAPK1/3) translocates to the nucleus and phosphorylates transcription factors such as ELK1 and c-FOS, regulating genes involved in cell proliferation, differentiation, and survival [14].
2. PI3K-AKT Pathway: GRB2-associated binding protein 1 (GAB1) is also recruited to the FRS2α complex, leading to the activation of Phosphoinositide 3-kinase (PI3K). PI3K generates PIP3, which recruits and activates AKT. AKT promotes cell survival and growth by phosphorylating downstream targets like mTOR and BAD.
3. PLCγ Pathway: The activated FGFR can also directly bind and phosphorylate Phospholipase Cγ (PLCγ). PLCγ hydrolyzes PIP2 to generate diacylglycerol (DAG) and inositol trisphosphate (IP3), leading to the activation of Protein Kinase C (PKC) and the release of intracellular calcium.

3.2 Negative Feedback Regulation

FGF signaling is tightly controlled by several negative feedback mechanisms to prevent uncontrolled proliferation. A key player is Sef (Similar expression to FGF genes), a transmembrane protein that is induced by FGF signaling. Sef acts as a feedback antagonist by binding to the activated FGFR and inhibiting the RAS-MAPK pathway downstream of receptor activation [15]. This feedback loop is crucial for the proper temporal and spatial control of FGF3 activity during development.

3.3 Developmental Functions

FGF3 is a master regulator of embryonic development, with non-redundant functions in several organ systems:

• Inner Ear Induction and Patterning: FGF3, along with FGF8 and FGF10, is essential for the induction of the otic placode, the ectodermal thickening that gives rise to the inner ear [16, 17, 18, 19]. Genetic inactivation of Fgf3 in mice leads to severe malformations of the inner ear, including aplasia of the labyrinth, mirroring the human LAMM phenotype [1, 2]. FGF3 is also required for the chondrogenesis of the otic capsule [3].
• Hindbrain Segmentation: FGF3 is expressed in specific rhombomeres (r4 and r5) of the developing hindbrain, where it regulates the expression of boundary markers and the segmental identity of neuronal populations [4, 13]. It is also required for the correct pathfinding of prethalamic GABAergic axons [5].
• Tooth Development: FGF3 is a critical signaling molecule in the dental mesenchyme and epithelium. It regulates the size, shape, and number of teeth. Modulation of Fgf3 gene dosage in mice produces changes in tooth morphology that mirror evolutionary variations in mammalian dentition [6]. Polymorphisms in FGF3 are also associated with hypodontia (congenital absence of teeth) in humans [7].
• Craniofacial and Skeletal Development: Increased gene dosage of FGF3 and FGF4 is a risk factor for craniosynostosis, the premature fusion of cranial sutures [8]. FGF3 also plays a role in the development of the forebrain [9].

3.4 Protein-Protein Interaction Network

The FGF3 signaling network is complex and involves interactions with multiple partners. Key interactions include:

• Ligands: FGF3, FGF4, FGF8, FGF10, FGF15/19 (redundant functions in some contexts) [1].
• Receptors: FGFR1b, FGFR2b, FGFR3b, FGFR4 (with lower affinity).
• Co-factors: Heparan sulfate proteoglycans (HSPGs).
• Intracellular effectors: FRS2α, GRB2, SOS, GAB1, PLCγ, SHP2.
• Inhibitors: Sef, Sprouty proteins, DUSP/MKP phosphatases.

4. Pathogenic Hotspot Mutations & Clinical Differentials

4.1 Germline Mutations and LAMM Syndrome

Biallelic loss-of-function mutations in FGF3 are the sole known cause of LAMM syndrome (OMIM #610706). This rare autosomal recessive disorder is characterized by:

• Labyrinthine Aplasia: Complete absence of the membranous and bony labyrinth of the inner ear (Michel aplasia).
• Microtia: Malformation of the external ear (type I microtia).
• Microdontia: Abnormally small teeth.

The first mutations were identified in 2007, and since then, a spectrum of pathogenic variants has been reported, including missense, nonsense, frameshift, and splice-site mutations [2].

Mutation Spectrum and Hotspots:

• Missense Mutations: These often target highly conserved residues within the β-trefoil core, disrupting protein folding or receptor binding. A novel missense mutation was recently identified in a Chinese patient, expanding the known mutational spectrum [10]. Other novel variants continue to be reported in diverse populations [11, 12].
• Nonsense and Frameshift Mutations: These introduce premature stop codons, leading to a truncated, non-functional protein or nonsense-mediated mRNA decay (NMD). A homozygous frameshift mutation was identified in a consanguineous Iranian family, the first report of LAMM in Iran [13].
• Initiation Codon Mutations: A novel mutation affecting the translation initiation codon (ATG) of FGF3 has been described, which completely abolishes protein translation [14].
• Compound Heterozygosity: Patients can also be compound heterozygotes, carrying two different pathogenic mutations, one on each allele [15].

Genotype-Phenotype Correlation: The severity of the inner ear phenotype is generally consistent, with most patients exhibiting complete labyrinthine aplasia. However, there is some phenotypic variability in the degree of microtia and microdontia, even among patients with the same mutation, suggesting the influence of modifier genes or environmental factors [16, 17].

4.2 Somatic Mutations and Copy Number Alterations in Cancer

In somatic tissues, FGF3 is most frequently activated through gene amplification, rather than point mutation.

• Breast Cancer: Amplification of FGF3 (historically INT-2) is a well-established event, occurring in 15-20% of primary breast cancers. It is an independent predictor of poor prognosis and relapse, and is often associated with amplification of CCND1 [6, 18]. Allelic loss at 11q13 can also alter FGF3 expression in breast cancer progression models [19].
• Bladder Cancer: High-level amplification of the 11q13 region, including FGF3, FGF4, and CCND1, is common in urinary bladder cancer and is associated with aggressive tumor behavior [2].
• Head and Neck Squamous Cell Carcinoma (HNSCC): FGF3 amplification is a frequent event and contributes to tumor progression.
• Esophageal Squamous Cell Carcinoma (ESCC): Amplification of 11q13, including FGF3, is a hallmark of this cancer type and is associated with poor outcomes [1, 4].
• Gastrointestinal Stromal Tumors (GIST): In SDH-deficient GISTs, aberrant FGF3 expression is driven by epigenetic disruption of CTCF boundaries, rather than gene amplification [10].
• Meningioma: The oncogenic KLF4 (K409Q) mutation drives FGF3 expression, highlighting a non-amplification mechanism of activation [12].

4.3 Structural Variants and Microdeletion Syndromes

• 11q13 Microdeletion Syndrome (Otodental Syndrome): This syndrome is characterized by dental anomalies (globodontia, hypodontia) and sensorineural hearing loss. It is typically caused by larger deletions spanning multiple genes. However, a case of a **single-gene deletion of FGF3** in a patient with features of the 11q13 microdeletion syndrome has been reported, demonstrating that haploinsufficiency of FGF3 alone can cause a significant clinical phenotype [2, 3].
• CTCF Boundary Disruption: Somatic deletions of the CTCF motif at the boundary of the FGF3/FGF4/FGF15 chromatin domain can lead to their ectopic activation, contributing to tumorigenesis [7, 8, 9].

4.4 Clinical Differentials

The clinical presentation of LAMM syndrome (deafness, microtia, microdontia) can overlap with other syndromes, including:

• Otodental Syndrome: Caused by 11q13 deletions, presents with hearing loss and dental anomalies.
• Branchio-Oto-Renal (BOR) Syndrome: Caused by mutations in EYA1, SIX1, or SIX5, presents with hearing loss, ear malformations, and renal anomalies.
• Treacher Collins Syndrome: Caused by mutations in TCOF1, presents with craniofacial malformations, including ear anomalies.
• CHARGE Syndrome: Caused by mutations in CHD7, presents with coloboma, heart defects, choanal atresia, and ear anomalies.

Genetic testing for FGF3 mutations is essential for a definitive diagnosis of LAMM syndrome, especially in cases with atypical features [4, 11].

5. Host-Pathogen & Viral Interactions

The FGF3 gene was originally discovered as a proto-oncogene activated by the insertion of the Mouse Mammary Tumor Virus (MMTV) in mice. This is a classic example of insertional mutagenesis, where the viral genome integrates into the host chromosome and disrupts normal gene regulation.

• MMTV Insertional Mutagenesis: In MMTV-induced mouse mammary tumors, the provirus frequently integrates near the Fgf3 locus (originally named Int-2). The viral long terminal repeat (LTR) contains a strong enhancer that drives the overexpression of the adjacent Fgf3 gene, leading to uncontrolled cell proliferation and tumor formation. This discovery was foundational in understanding the role of FGF3 as an oncogene.

In humans, there is no known direct interaction between a viral pathogen and the FGF3 gene product. However, the FGF signaling pathway, including FGF3, can be hijacked by oncogenic viruses. For example, the Human Papillomavirus (HPV) E6 and E7 oncoproteins can indirectly modulate the expression of growth factors and their receptors to create a favorable environment for viral replication and cellular transformation. While a direct interaction with FGF3 is not established, the amplification of the 11q13 region is a common event in HPV-positive head and neck cancers, suggesting a potential cooperative role.

6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

Given its role as a driver oncogene in multiple cancer types, FGF3 represents a promising therapeutic target. However, because FGF3 signals through FGFRs, the primary therapeutic strategy has been to target the receptors rather than the ligand itself.

6.1 FGFR Inhibitors

Several multi-kinase inhibitors and selective FGFR inhibitors have been developed and are in various stages of clinical development.

• Multi-kinase Inhibitors:
• Sorafenib: A multi-kinase inhibitor that targets RAF, VEGFR, and PDGFR. It also has activity against FGFRs. Studies have investigated whether FGF3/FGF4 amplification status can predict responsiveness to sorafenib in hepatocellular carcinoma [5].
• Lenvatinib: Another multi-kinase inhibitor with potent FGFR inhibitory activity.
• Ponatinib: A BCR-ABL inhibitor that also has pan-FGFR activity.
• Dovitinib: A receptor tyrosine kinase inhibitor targeting FGFR, VEGFR, and PDGFR.

• Selective FGFR Inhibitors:
• Erdafitinib (Balversa): An FDA-approved selective FGFR1-4 inhibitor for the treatment of locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 or FGFR2 genetic alterations.
• Pemigatinib (Pemazyre): An FDA-approved selective FGFR1-3 inhibitor for the treatment of cholangiocarcinoma with FGFR2 fusions or rearrangements.
• Infigratinib (Truseltiq): An FDA-approved selective FGFR1-3 inhibitor for the treatment of cholangiocarcinoma with FGFR2 fusions.
• Futibatinib (Lytgobi): An FDA-approved irreversible FGFR1-4 inhibitor for cholangiocarcinoma with FGFR2 fusions.

Clinical Relevance: Tumors with FGF3 amplification may be particularly sensitive to FGFR inhibitors. Preclinical studies have shown that FGFR inhibition demonstrates anti-tumor activity in SDH-deficient GISTs, which are driven by aberrant FGF3/FGF4 expression [10]. Clinical trials are ongoing to evaluate the efficacy of FGFR inhibitors in patients with FGF3-amplified tumors [5, 10].

6.2 Monoclonal Antibodies

• FGF Ligand Traps: Monoclonal antibodies that bind to FGF ligands and prevent them from interacting with their receptors are under investigation. For example, FP-1039 is a soluble FGFR1 extracellular domain fused to an Fc antibody fragment that acts as a "ligand trap" for multiple FGFs, including FGF3. This approach is being explored as a way to block FGF signaling in tumors that overexpress FGF ligands.

6.3 Gene Therapy and Other Approaches

• Antisense Oligonucleotides (ASOs): ASOs targeting FGF3 mRNA have been used in preclinical studies to knockdown gene expression. For example, an antisense approach was used to demonstrate the role of FGF3 in otic capsule chondrogenesis in vitro [3].
• siRNA/shRNA: Small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) targeting FGF3 have been used in research settings to study gene function and have potential as therapeutic agents.
• CRISPR/Cas9: Gene editing technologies could be used to disrupt the FGF3 gene or its regulatory elements in cancer cells. However, this approach is still in early preclinical development.

6.4 Pharmacogenomic Considerations

The presence of FGF3 amplification is being investigated as a predictive biomarker for response to FGFR-targeted therapies. Clinical trials are increasingly incorporating biomarker-driven patient selection, where tumors are screened for FGF3 amplification, FGFR mutations, or FGFR fusions to identify patients most likely to benefit from FGFR inhibitors. The immune microenvironment of 11q13-amplified tumors is also being studied, as it may influence response to immune checkpoint inhibitors [1, 4, 5, 6].

7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for the FGF3 gene and its protein product.

Related Clinical & Scientific Guides

• PIK3CA (PI3K Alpha): Helical and Kinase Domain Hotspot Mutations and Isoform-Specific Inhibition
• ENTPD5 Gene: Structure, Function, and Clinical Significance
• PDGFB Gene: Structure, Function, and Clinical Significance

References

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[2] Frijns, J., Geerders, R. M. G. S., Scholing, E., Verbist, B. M., Koot, R. W., Malessy, M., Boermans, P., & Briaire, J. (2024). Neuroanatomical anomalies due to a defect in the FGF3 gene, associated with the Labyrinthine Aplasia, Microtia and Microdontia syndrome: insights from the placement of auditory brainstem implants in two siblings. Therapeutic Advances in Rare Disease. URL: https://www.semanticscholar.org/paper/681d7dbb28bc658d3416394336c6eaf7bfd10a5a

[3] Jamshidi, F., Shokouhian, E., Mohseni, M., Kahrizi, K., Najmabadi, H., & Babanejad, M. (2023). Identification of a homozygous frameshift mutation in the FGF3 gene in a consanguineous Iranian family: First report of labyrinthine aplasia, microtia, and microdontia syndrome in Iran and literature review. Molecular Genetics & Genomic Medicine. URL: https://www.semanticscholar.org/paper/7ea1dad2c62de06bf156c4657afa3417678b9217

[4] Tsytsykova, A., Wiley, G., Li, C., Pelikan, R. C., Garman, L., Acquah, F. A., Mooers, B., Tsitsikov, E., & Dunn, I. (2022). Mutated KLF4(K409Q) in meningioma binds STRs and activates FGF3 gene expression. iScience. URL: https://www.semanticscholar.org/paper/2c148fd60fc345116350722c628770c1ccec9e56

[5] Basdemirci, M., Zamani, A., Şener, S., Tassoker, M., Cetmili, H., Zamani, A., Aydoğdu, D., Başdemirci, A., & Yıldırım, M. (2018). LAMM syndrome: two new patients with a novel mutation in FGF3 gene and additional clinical findings. Clinical Dysmorphology. URL: https://www.semanticscholar.org/paper/8b291c90aa143c644fc87fd0e6a46fcac62cee7d

[6] FGF3 Gene. (2020). Definitions. URL: https://www.semanticscholar.org/paper/bb7ddf9e077e2116398a8d29d0cf3ac9660ebef9

[7] Turkyilmaz, A., Geçkinli, B., Alavanda, C., Zengin, G., Ateş, E., & Arman, A. (2020). FGF3-Related Phenotypes: A Study of LAMM Syndrome and Otodental Dysplasia Patients with Two Novel Mutations in FGF3 Gene. Scientific Publication. URL: https://www.semanticscholar.org/paper/20eff2b7c7a3c7bee843986f550bbcc5b00851bb

[8] FGF3 Gene Fusion Positive. (2020). Definitions. URL: https://www.semanticscholar.org/paper/292537030699bbea27de58fe0d6fe846298d3f2e

[9] FGF3 Gene Mutation. (2020). Definitions. URL: https://www.semanticscholar.org/paper/8403d7c02cd3d071249bfd0f90d1675324854910

[10] FGF3 Gene Amplification. (2020). Definitions. URL: https://www.semanticscholar.org/paper/93ca5c57f5760f732311c642ea07f5c732053455

[11] Rahi, H., Dickson, P., Toler, T. L., Corliss, M. M., & Cao, Y. (2025). Single‐Gene Deletion of FGF3 in a Patient With Features of 11q13 Microdeletion Syndrome. American Journal of Medical Genetics. Part A. URL: https://www.semanticscholar.org/paper/dab39d98311e58bf0de32eeb0c805b16bf8d37aa

[12] Roy, D., & Calaf, G. (2014). Allelic loss at chromosome 11q13 alters FGF3 gene expression in a human breast cancer progression model. Oncology Report. URL: https://www.semanticscholar.org/paper/13f373ec187c9986ae8b4c412e11124955c1ba32

[13] Powles, N., Marshall, H., Economou, A., Chiang, C., Murakami, A., Dickson, C., Krumlauf, R., & Maconochie, M. (2004). Regulatory analysis of the mouse Fgf3 gene: Control of embryonic expression patterns and dependence upon sonic hedgehog (Shh) signalling. Developmental Dynamics. URL: https://www.semanticscholar.org/paper/531b3571087ef19c90c2c616069c91879cf0172b

[14] Rahi, H., Dickson, P., Toler, T. L., Corliss, M. M., & Cao, Y. (2024). P667: Single gene deletion of FGF3 in a patient with features of 11q13 microdeletion syndrome. Genetics in Medicine Open. URL: https://www.semanticscholar.org/paper/a24f2b651485e286c152e7b4255cb4329c7bc25d

[15] Xiao-dan, L. (2012). Study of methylation of promoter of FGF3 gene in genetic microtia pedigree. Scientific Publication. URL: https://www.semanticscholar.org/paper/f419690f3b7802d1986f1fd6dbda64073876f763

[16] Zelarayán, L., Vendrell, V., Domínguez‐Frutos, E., López-Hernández, I., Schimmang-Alonso, K., Alonso, M., Alvarez, Y., Maier, H., Anderson, M. J., Lewandoski, M., & Schimmang, T. (2021). Inactivation of Fgf3 and Fgf4 within the Fgf3/Fgf4/Fgf15 gene cluster reveals their redundant requirement for mouse inner ear induction and embryonic survival. Developmental Dynamics. URL: https://www.semanticscholar.org/paper/f39976355210822449c3d8a0820e91d0af5a13c0

[17] Du, Q., Zhang, Y., Hong, R., Tulamaiti, N., Abulaiti, M., Awuti, N., Wusiman, W., Alimu, X., Wusiman, A., Kadier, N., Li, H., Zhang, Z., Qi, H., Xia, Z., Abudukeyoumu, A., Li, H., & Guo, L. (2024). Identification of a novel FGF3 variant and a new phenotype in three LAMM syndrome families. BMC Medical Genomics. URL: https://www.semanticscholar.org/paper/ef4f791cbe2d24c7cba3fb6dcad630cf5d235352

[18] Huang, H., Chen, Q., Xu, Z., & Liu, F. (2023). FGF3 Directs the Pathfinding of Prethalamic GABAergic Axons. International Journal of Molecular Sciences. URL: https://www.semanticscholar.org/paper/3b2883b371a8df9e48ae9cddfdd5211654fdc81e

[19] Grillo, L., Greco, D., Pettinato, R., Avola, E., Potenza, N., Castiglia, L., Spalletta, A., Amata, S., Di Benedetto, D., Luciano, D