FGFRL1

FGFRL1 (Fibroblast Growth Factor Receptor Like 1) is a unique member of the FGFR family that lacks intracellular kinase activity and instead plays regulatory roles in growth factor signaling, cell adhesion, and tissue development. 

It is essential for normal formation of the skeleton, kidneys, and diaphragm, and emerging research suggests it may also influence cancer progression and congenital disorders.

What is FGFRL1 (Fibroblast Growth Factor Receptor Like 1)?

FGFRL1 (also known as FHFR, FGFR5, and FGFR-5) is a gene located on chromosome 4p16.3 that encodes the fibroblast growth factor receptor-like 1 protein. 

It belongs to the FGFR (fibroblast growth factor receptor) family, but unlike FGFR1–4, FGFRL1 lacks the typical intracellular tyrosine kinase domain. Instead, it has a short cytoplasmic tail with a histidine-rich region and tyrosine-based motifs, which give it distinct biological functions.

Gene and Protein Characteristics

Structure: The protein structure includes three extracellular immunoglobulin-like domains, a transmembrane domain, and a short intracellular tail (no kinase activity).

Expression: FGFRL1 is primarily expressed in fetal tissues rich in cartilage, such as developing bone, vertebrae, and the whole embryo.

Binding Partners: The protein binds multiple FGF ligands (especially FGF3, FGF8, and FGF10, as well as other proteins) and heparin with high affinity.

Functional Differences from FGFRs

The FGFRL1 protein does not activate classical signaling pathways (like MAPK or PI3K/AKT) through phosphorylation.

Instead, it is thought to modulate FGF signaling by acting as a decoy receptor or by regulating receptor internalization and ligand availability.

Mechanisms of Action

FGFRL1 influences cell behavior in several ways:

• Ligand Regulation: Binds and sequesters FGF ligands, limiting their availability to signaling FGFRs.
• Cell Adhesion and Fusion: Promotes early cell-cell adhesion and can drive cell fusion in vitro.
• Differentiation Support: Encourages differentiation of muscle and skeletal cells while suppressing excessive cell proliferation.
• Internalization: The intracellular tail helps regulate receptor recycling and degradation via endosomal pathways.

Role in Biological Processes

FGFRL1 is active in tissues undergoing development or structural remodeling. Key roles include:

• Kidney Development: Essential for nephron formation; knockout mice lack kidneys and die at birth.
• Skeletal Development: Highly expressed in cartilage; contributes to bone and craniofacial growth.
• Diaphragm Formation: Required for proper muscle development in the diaphragm.
• Tumor Regulation: Acts as a growth suppressor in some cancers, but may also support tumor progression under certain conditions.
• Growth Factor Signalling Affects Height, Blood Pressure, and Bone Health: In a large Korean population study, Variations in the FGFRL1 gene were linked to increased or decreased risk of hypertension and osteoporosis. FGFRL1 interacts with several FGF genes and may influence both cardiovascular and skeletal systems through its effects on growth factor signaling.

Conditions Associated with FGFRL1 Genetic Mutations

Although FGFRL1 mutations are rare, studies in both humans and animals show that changes in this gene can lead to problems with development, especially in the bones, kidneys, and diaphragm. Researchers have also found links between FGFRL1 and certain types of cancer.

Craniosynostosis and Skeletal Anomalies

A rare mutation in the FGFRL1 gene has been found in a person with craniosynostosis, a condition where the bones in the skull fuse too early. This patient also had joint and genital abnormalities. 

The mutation may have caused gene overexpression, leading to abnormal bone development.

Bilateral Renal Agenesis

In animal studies, mice missing the FGFRL1 gene were born without kidneys and died shortly after birth. This shows the gene is essential for kidney development. 

While this has not yet been confirmed in humans, FGFRL1 may be important in cases of unexplained kidney absence.

Congenital Diaphragmatic Hernia

FGFRL1 helps form the diaphragm, the muscle used for breathing. Mice without FGFRL1 have weak or missing diaphragm muscles and cannot breathe properly at birth. 

In humans, certain gene variants may raise the risk of congenital diaphragmatic hernia, especially in people missing part of chromosome 4p16.3, where FGFRL1 is located.

Wolf-Hirschhorn Syndrome (4p16.3 Deletion Syndrome)

Wolf-Hirschhorn syndrome is a condition caused by missing genes on chromosome 4. FGFRL1 is in this region and may contribute to the syndrome’s facial features and bone problems. 

Although FGFRL1 alone may not cause the condition, losing it could add to the severity of symptoms.

Cancer Associations

FGFRL1 levels can be higher or lower in different cancers, such as prostate, ovarian, and esophageal cancers. 

In some cases, high FGFRL1 levels may make cancer more aggressive, while in others, lower levels may reduce the body’s ability to control cell growth. FGFRL1 may affect cancer by interacting with pathways that control how cells grow and divide.

When is FGFRL1 Genetic Analysis Relevant?

FGFRL1 genetic testing may be considered in the following settings: 

Genetic Research Studies

FGFRL1 is primarily studied in the context of:

• Craniofacial and skeletal malformations (e.g., craniosynostosis)
• Kidney agenesis and congenital diaphragm defects
• Cancer biology and tumor suppressor pathways

Not Routinely Clinically Tested

FGFRL1 testing is not part of standard clinical panels. Instead, it may be included in research settings or when exploring syndromic causes of developmental disorders.

What Do Specific FGFRL1 Genetic Variations Mean?

Specific FGFRL1 gene mutations may carry clinical relevance:

Disease Associations (Research Context)

Gain-of-function variants (e.g., frameshift in intracellular domain) may contribute to craniosynostosis.

Loss-of-function (knockouts in animal models) lead to lethal developmental defects like kidney agenesis and diaphragm hypoplasia.

Emerging Cancer Relevance

Research indicates that FGFRL1 expression is altered in various cancers, including prostate and ovarian cancer.

It may suppress tumor growth in some contexts but contribute to invasiveness in others via PI3K/Akt or MAPK signaling.

What Does the Absence of Specific FGFRL1 Variants Mean?

Does not rule out FGF pathway involvement: Other FGFRs and FGF genes may still play a role in disease.

Limited predictive value in isolation: Variants must be interpreted alongside clinical findings, family history, and environmental factors.

Test Procedure and Interpretation

Testing for FGFRL1 is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for FGFRL1 genetic testing are considered to be without mutations that can alter the activity of the FGFRL1 proteins.

Clinical Implications of Positive FGFRL1 Mutations

The clinical implications of a positive FGFRL1 mutation test result will vary by individual, although FGFRL1 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of congenital skeletal or breathing problems, or other symptoms.

Patients or practitioners with questions about the clinical implications of FGFRL1 mutations should seek further assessment with a genetic counselor or expert. 

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