Association of folate receptor (folr1, folr2, folr3) and reduced folate carrier (slc19a1) genes with meningomyelocele

O'Byrne, Michelle R.; Au, Kit Sing; Morrison, Alanna C.; Lin, Jone Ing; Fletcher, Jack Μ.; Ostermaier, Kathryn K.; Tyerman, Gayle H.; Doebel, Sabine

doi:10.1002/bdra.20706

Cited by 38 publications

(30 citation statements)

References 38 publications

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“…The importance of folate uptake systems for the formation of the neural tube has been shown by studies in humans and mice. Significant associations between single-nucleotide polymorphisms (SNPs) in different human folate transporters and myelomeningocele compared with the ethnically paired healthy population have been found, including one SNP in FOLR1, two in FOLR2, five in FOLR3 and two in the reduced folate carrier (O'Byrne et al, 2010). In mice, knockout of Folr1 results in an open neural tube by embryonic day 9.5, when heterozygotes or wild-type littermate embryos show a closed neural tube.…”

Section: Introductionmentioning

confidence: 99%

Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation

2017

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Folate supplementation prevents up to 70% of neural tube defects (NTDs), which result from a failure of neural tube closure during embryogenesis. The elucidation of the mechanisms underlying folate action has been challenging. This study introduces Xenopus laevis as a model to determine the cellular and molecular mechanisms involved in folate action during neural tube formation. We show that knockdown of folate receptor 1 (Folr1; also known as FRα) impairs neural tube formation and leads to NTDs. Folr1 knockdown in neural plate cells only is necessary and sufficient to induce NTDs. Folr1-deficient neural plate cells fail to constrict, resulting in widening of the neural plate midline and defective neural tube closure. Pharmacological inhibition of folate action by methotrexate during neurulation induces NTDs by inhibiting folate interaction with its uptake systems. Our findings support a model in which the folate receptor interacts with cell adhesion molecules, thus regulating the apical cell membrane remodeling and cytoskeletal dynamics necessary for neural plate folding. Further studies in this organism could unveil novel cellular and molecular events mediated by folate and lead to new ways of preventing NTDs.

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Section: Introductionmentioning

confidence: 99%

Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation

2017

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“…Folate can also be transported across cellular membranes using the folate receptor-β, 27 the reduced folate carrier (RFC) 28 and the proton-coupled folate transporter. 29 Although folate receptor-β seems important in the placental transport of folate, 27 the proton-coupled folate transporter is critical in folate transport in the gastrointestinal tract especially as impairment of this transporter function is responsible for hereditary folate malabsorption.…”

Section: Introductionmentioning

confidence: 99%

Cerebral folate receptor autoantibodies in autism spectrum disorder

et al. 2012

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Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood–brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg−1 per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

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“…FOLR1, also identified as FBP, is encoded by FOLR1, which is located on chromosome 11q13.4 [33]. It is a variably expressed glycosylated membrane-associated protein present in the outer layer of the plasma membrane facilitating unidirectional transport of folic acid, 5-methyltetrahydrofolate and MTX [33].…”

Section: Folr1mentioning

confidence: 99%

“…It is a variably expressed glycosylated membrane-associated protein present in the outer layer of the plasma membrane facilitating unidirectional transport of folic acid, 5-methyltetrahydrofolate and MTX [33]. While folates enter primarily by FOLR1, MTX enters the cell primarily by SLC19A1-mediated transport [7].…”

Section: Folr1mentioning

confidence: 99%

Genetic Polymorphisms in Low-Dose Methotrexate Transporters: Current Relevance as Methotrexate Therapeutic Outcome Biomarkers

et al. 2014

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Methotrexate (MTX) is used in low doses to treat a variety of diseases. Although the mechanism responsible for its therapeutic action is unknown, MTX membrane transport proteins (influx and/or efflux) can be major determinants of pharmacokinetics, adverse drug reactions and clinical response profiles. With progess in pharmacogenomics, the improvement of the prediction of patients' therapeutic outcome treated with low doses of MTX will offer a powerful tool for the translation of transporter SNPs into clinical practice and will be essential to sustain a breakthrough in the field of personalized medicine. Therefore, this paper provides an update on the current data on SNPs in genes encoding low-dose MTX membrane transport proteins and their relevance as possible biomarkers of MTX therapeutic outcome.

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Association of folate receptor (folr1, folr2, folr3) and reduced folate carrier (slc19a1) genes with meningomyelocele

Cited by 38 publications

References 38 publications

Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation

Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation

Cerebral folate receptor autoantibodies in autism spectrum disorder

Genetic Polymorphisms in Low-Dose Methotrexate Transporters: Current Relevance as Methotrexate Therapeutic Outcome Biomarkers

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