The FOLR1 gene encodes folate receptor alpha (FRα), a high-affinity transporter responsible for delivering active folate into cells—especially those in the brain and certain epithelial tissues.
This receptor plays a vital role in both neurodevelopment and cancer biology, making FOLR1 a key gene of interest in rare neurological disorders and as a therapeutic target in several malignancies.
The FOLR1 gene provides the blueprint for a protein called folate receptor alpha (FRα)—a cell surface receptor responsible for transporting folate (vitamin B9) into cells. Folate is essential for DNA synthesis and repair, red blood cell production, and nervous system health.
While folate circulates freely in the bloodstream, FRα plays a key role in helping specific tissues—especially the brain—absorb and use it effectively.
FOLR1 encodes folate receptor alpha, a glycosylphosphatidylinositol (GPI)-anchored protein located on the surface of certain epithelial cells.
It binds with high affinity to 5-methyltetrahydrofolate (5-MTHF), the active form of folate, and brings it into cells through a process known as receptor-mediated endocytosis.
Folate taken up through FRα is vital for:
Although other folate transporters exist (such as the reduced folate carrier), FRα plays a unique and critical role in transporting folate into certain protected areas, especially the central nervous system (CNS).
FRα is selectively expressed in:
This restricted expression pattern in healthy tissue makes FRα a promising therapeutic target, particularly in oncology.
FOLR1 testing may be relevant in the following scenarios:
FOLR1 can be important in cancer diagnosis and treatment.
FOLR1 is overexpressed in up to 80% of nonmucinous epithelial ovarian cancers. This overexpression enables targeted drug delivery using folate-linked chemotherapies and monoclonal antibodies.
FOLR1 is also being investigated as a biomarker and therapeutic target in:
FOLR1 testing (via immunohistochemistry or molecular methods) may help identify patients who are candidates for FOLR1-targeted therapies, such as antibody-drug conjugates (e.g., mirvetuximab, soravtansine) or folate–drug conjugates.
Neurological manifestations of FOLR1 deficiency can include cerebral folate transport deficiency.
Mutations in FOLR1 can cause cerebral folate deficiency, a rare inherited disorder that results in low CSF folate levels despite normal blood folate. It typically presents in early childhood with:
Prompt treatment with high-dose folinic acid (5-formyltetrahydrofolate) can improve or stabilize symptoms. Avoid folic acid, which may inhibit FRα function.
Therapeutic Opportunity: High expression indicates the tumor may respond to FOLR1-targeted therapies such as antibody-drug conjugates or folate-conjugated chemotherapeutics.
Prognostic Marker: Studies suggest high FOLR1 expression is associated with higher tumor grade, chemoresistance, and shorter survival in some cancers. Its persistent expression in metastatic tissue makes it a potential marker for recurrence monitoring.
Reduced Benefit from Targeted Therapy: Tumors lacking FOLR1 expression are unlikely to respond to therapies that rely on FRα for drug delivery.
Alternative Strategies Needed: Other therapeutic approaches—such as immunotherapy or non-targeted chemotherapy—should be considered.
FOLR1 (FRα) is a high-affinity folate transporter essential for brain development and a promising target in epithelial cancers.
Cerebral folate deficiency due to FOLR1 mutations should be considered in children with developmental regression, seizures, and unexplained leukodystrophy, especially if serum folate is normal but CSF folate is low.
In oncology, FOLR1 testing can support patient stratification for targeted therapies, especially in ovarian, endometrial, breast, and lung cancers.
FOLR1-targeted therapies are generally well tolerated, with low off-target toxicity due to the limited expression of this gene in normal adult tissues.
Molecular testing, especially for tumors or suspected CFD, is key to personalized care.
Testing for FOLR1 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.
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 for FOLR1 genetic testing are considered to be without mutations that can alter the activity of the FOLR1 proteins.
The clinical implications of a positive FOLR1 mutation test result will vary by individual, although FOLR1 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various cancers and/or symptoms.
Patients or practitioners with questions about the clinical implications of FOLR1 mutations should seek further assessment with a genetic counselor or expert.
Click here to compare genetic test panels and order genetic testing for health-related SNPs.
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