The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption

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Abstract

The proton-coupled folate transporter (PCFT-SLC46A1) is the mechanism by which folates are absorbed across the brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder "hereditary folate malabsorption" (HFM), results in a syndrome characterized by severe systemic and cerebral folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in "cerebral folate deficiency" (CFD), the designation for this disorder. This paper reviews the current understanding of the functional and structural properties and regulation of PCFT, an electrogenic proton symporter, and contrasts PCFT properties with those of the reduced folate carrier (RFC), an organic anion antiporter, that is the major route of folate transport to systemic tissues. The clinical characteristics of HFM and its treatment, based upon the thirty-seven known cases with the clinical syndrome, of which thirty have been verified by genotype, are presented. The ways in which PCFT and FRα might interact at the level of the choroid plexus such that each is required for folate transport from blood to cerebrospinal fluid are considered along with the different clinical presentations of HFM and CFD.

Original languageEnglish (US)
JournalMolecular Aspects of Medicine
DOIs
StateAccepted/In press - May 16 2016

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Proton-Coupled Folate Transporter
Folic Acid
Choroid Plexus
Folate Receptor 1
Cerebrospinal fluid
Cerebrospinal Fluid
Reduced Folate Carrier Protein
Antiporters
Symporters
Microvilli
Hereditary Folate Malabsorption
Small Intestine
Anions
Protons
Brushes
Genotype

Keywords

  • 5-Formyltetrahydrofolate (PubChem CID: 143)
  • 5-Methyltetrahydrofolate (PubChem CID: 439234)
  • Cerebral folate deficiency
  • CFD
  • Folate receptors
  • Folates
  • Folic acid
  • Folic acid (PubChem CID: 6037)
  • FRα
  • Hereditary folate malabsorption
  • HFM
  • Levoleucovorin (PubChem CID: 149436)
  • Levomefolic acid (PubChem CID: 444412)
  • Methotrexate
  • Methotrexate (PubChem CID: 126941)
  • PCFT
  • Pemetrexed
  • Pemetrexed (PubChem CID: 446556)
  • Proton-coupled folate transporter
  • Reduced folate carrier
  • RFC
  • SLC19A1
  • SLC46A1

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

@article{2dd23d5c16584c7591e21480f068c471,
title = "The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption",
abstract = "The proton-coupled folate transporter (PCFT-SLC46A1) is the mechanism by which folates are absorbed across the brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder {"}hereditary folate malabsorption{"} (HFM), results in a syndrome characterized by severe systemic and cerebral folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in {"}cerebral folate deficiency{"} (CFD), the designation for this disorder. This paper reviews the current understanding of the functional and structural properties and regulation of PCFT, an electrogenic proton symporter, and contrasts PCFT properties with those of the reduced folate carrier (RFC), an organic anion antiporter, that is the major route of folate transport to systemic tissues. The clinical characteristics of HFM and its treatment, based upon the thirty-seven known cases with the clinical syndrome, of which thirty have been verified by genotype, are presented. The ways in which PCFT and FRα might interact at the level of the choroid plexus such that each is required for folate transport from blood to cerebrospinal fluid are considered along with the different clinical presentations of HFM and CFD.",
keywords = "5-Formyltetrahydrofolate (PubChem CID: 143), 5-Methyltetrahydrofolate (PubChem CID: 439234), Cerebral folate deficiency, CFD, Folate receptors, Folates, Folic acid, Folic acid (PubChem CID: 6037), FRα, Hereditary folate malabsorption, HFM, Levoleucovorin (PubChem CID: 149436), Levomefolic acid (PubChem CID: 444412), Methotrexate, Methotrexate (PubChem CID: 126941), PCFT, Pemetrexed, Pemetrexed (PubChem CID: 446556), Proton-coupled folate transporter, Reduced folate carrier, RFC, SLC19A1, SLC46A1",
author = "Rongbao Zhao and Srinivas Aluri and Goldman, {I. David}",
year = "2016",
month = "5",
day = "16",
doi = "10.1016/j.mam.2016.09.002",
language = "English (US)",
journal = "Molecular Aspects of Medicine",
issn = "0098-2997",
publisher = "Elsevier Limited",

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TY - JOUR

T1 - The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy

T2 - Hereditary folate malabsorption

AU - Zhao, Rongbao

AU - Aluri, Srinivas

AU - Goldman, I. David

PY - 2016/5/16

Y1 - 2016/5/16

N2 - The proton-coupled folate transporter (PCFT-SLC46A1) is the mechanism by which folates are absorbed across the brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder "hereditary folate malabsorption" (HFM), results in a syndrome characterized by severe systemic and cerebral folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in "cerebral folate deficiency" (CFD), the designation for this disorder. This paper reviews the current understanding of the functional and structural properties and regulation of PCFT, an electrogenic proton symporter, and contrasts PCFT properties with those of the reduced folate carrier (RFC), an organic anion antiporter, that is the major route of folate transport to systemic tissues. The clinical characteristics of HFM and its treatment, based upon the thirty-seven known cases with the clinical syndrome, of which thirty have been verified by genotype, are presented. The ways in which PCFT and FRα might interact at the level of the choroid plexus such that each is required for folate transport from blood to cerebrospinal fluid are considered along with the different clinical presentations of HFM and CFD.

AB - The proton-coupled folate transporter (PCFT-SLC46A1) is the mechanism by which folates are absorbed across the brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder "hereditary folate malabsorption" (HFM), results in a syndrome characterized by severe systemic and cerebral folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in "cerebral folate deficiency" (CFD), the designation for this disorder. This paper reviews the current understanding of the functional and structural properties and regulation of PCFT, an electrogenic proton symporter, and contrasts PCFT properties with those of the reduced folate carrier (RFC), an organic anion antiporter, that is the major route of folate transport to systemic tissues. The clinical characteristics of HFM and its treatment, based upon the thirty-seven known cases with the clinical syndrome, of which thirty have been verified by genotype, are presented. The ways in which PCFT and FRα might interact at the level of the choroid plexus such that each is required for folate transport from blood to cerebrospinal fluid are considered along with the different clinical presentations of HFM and CFD.

KW - 5-Formyltetrahydrofolate (PubChem CID: 143)

KW - 5-Methyltetrahydrofolate (PubChem CID: 439234)

KW - Cerebral folate deficiency

KW - CFD

KW - Folate receptors

KW - Folates

KW - Folic acid

KW - Folic acid (PubChem CID: 6037)

KW - FRα

KW - Hereditary folate malabsorption

KW - HFM

KW - Levoleucovorin (PubChem CID: 149436)

KW - Levomefolic acid (PubChem CID: 444412)

KW - Methotrexate

KW - Methotrexate (PubChem CID: 126941)

KW - PCFT

KW - Pemetrexed

KW - Pemetrexed (PubChem CID: 446556)

KW - Proton-coupled folate transporter

KW - Reduced folate carrier

KW - RFC

KW - SLC19A1

KW - SLC46A1

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U2 - 10.1016/j.mam.2016.09.002

DO - 10.1016/j.mam.2016.09.002

M3 - Article

C2 - 27664775

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JO - Molecular Aspects of Medicine

JF - Molecular Aspects of Medicine

SN - 0098-2997

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