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FOLR1
folate receptor alpha
The FOLR1 gene provides instructions for producing folate receptor alpha, a protein essential for transporting the B-vitamin folate into cells, particularly within the brain. Folate receptor alpha, encoded by the FOLR1 gene, plays a critical role in cellular folate uptake.
FOLR1 is located on the long (q) arm of chromosome 11, at band 11q13.4. Arm ratio per GRCh38 - banding schematic.
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Overview
The FOLR1 gene encodes folate receptor alpha, a protein vital for regulating the transport of the B-vitamin folate (also known as vitamin B9) into cells throughout the body. Folate is a crucial nutrient involved in numerous biological processes, including DNA production and repair, gene activity regulation, and protein synthesis. A well-functioning folate transport system, facilitated by FOLR1, is therefore fundamental for overall cellular health.
What the gene does
The folate receptor alpha protein is situated within the cell membrane, where it specifically binds to a form of folate called 5-methyl-tetrahydrofolate (5-MTHF). This binding action allows 5-MTHF to be efficiently transported from the bloodstream into the cell. While folate receptor alpha is found in various tissues, its production is particularly high in the brain, especially in the choroid plexus. This region is responsible for producing cerebrospinal fluid (CSF), which surrounds and protects the brain and spinal cord. Within the brain, folate is indispensable for creating neurotransmitters, which are chemical messengers, and myelin, a fatty substance that insulates nerve fibres and supports rapid nerve impulse transmission. Folate receptor alpha plays a major role in moving folate from the bloodstream, across the choroid plexus, and into the CSF, thereby ensuring adequate folate levels reach brain cells.
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Chromosome location
The FOLR1 gene is located on chromosome 11, specifically at position 11q13.4. This chromosomal region is a specific band on the long arm of chromosome 11.
Protein structure
The FOLR1 gene encodes a protein composed of 257 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the FOLR1 gene can affect the production or function of the folate receptor alpha protein. These genetic changes can lead to a deficiency in the protein or result in a protein that does not function correctly, thereby impairing cellular folate uptake. The impact of these variants can vary depending on their specific nature and location within the gene.
Sample of pathogenic variants
2 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
g.(?_71903218)_(71903405_?)del | - | Pathogenic | ★☆☆☆ | Cerebral folate transport deficiency |
g.(?_71906295)_(71907221_?)del | - | Pathogenic | ★☆☆☆ | Cerebral folate transport deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Genetic changes in the FOLR1 gene have been identified as a cause of cerebral folate transport deficiency. This condition is characterised by neurological problems that typically manifest around two years of age, stemming from insufficient folate levels within the brain despite normal folate levels elsewhere in the body.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FOLR1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The FOLR1 gene is recognised in the UK's NHS Genomic Medicine Service, being listed on several PanelApp panels. These include 'Ataxia and cerebellar anomalies - childhood onset', 'Cerebral folate deficiency', 'DDG2P', 'Dystonia, chorea or related movement disorder, childhood onset', 'Early onset or syndromic epilepsy', 'Foetal anomalies', 'Hereditary ataxia', 'Hereditary ataxia, adult onset', 'Inherited white matter disorders', 'Intellectual disability', 'Likely inborn error of metabolism', 'Neurotransmitter disorders', 'Undiagnosed metabolic disorders', and 'White matter disorders and cerebral calcification - childhood onset', all of which are rated 'green', indicating sufficient evidence for gene-disease association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the FOLR1 gene?
The FOLR1 gene provides instructions for making folate receptor alpha, a protein crucial for transporting the B-vitamin folate into cells, particularly within the brain and cerebrospinal fluid.
Why is folate important for brain function?
In the brain, folate is essential for the production of neurotransmitters, which are chemical messengers, and myelin, which insulates nerve fibres and facilitates rapid signal transmission.
What happens if the FOLR1 gene doesn't work correctly?
If the FOLR1 gene is not functioning correctly, it can lead to impaired folate transport into cells, especially brain cells, potentially causing conditions like cerebral folate transport deficiency, which involves neurological problems.
References
- Grapp M, Wrede A, Schweizer M. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nature communications. 2013. PMID: 23828504
- Watkins D, Rosenblatt DS. Update and new concepts in vitamin responsive disorders of folate transport and metabolism. Journal of inherited metabolic disease. 2012. PMID: 22108709
- Pérez-Dueñas B, Toma C, Ormazábal A. Progressive ataxia and myoclonic epilepsy in a patient with a homozygous mutation in the FOLR1 gene. Journal of inherited metabolic disease. 2010. PMID: 20857335
- Steinfeld R, Grapp M, Kraetzner R. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. American journal of human genetics. 2009. PMID: 19732866
- Cario H, Bode H, Debatin KM. Congenital null mutations of the FOLR1 gene: a progressive neurologic disease and its treatment. Neurology. 2009. PMID: 20018644