Functional roles of the A335 and G338 residues of the proton-coupled folate transporter (PCFT-SLC46A1) mutated in hereditary folate malabsorption

Shin, Daniel Sanghoon; Zhao, Rongbao; Fiser, András; Goldman, David

doi:10.1152/ajpcell.00171.2012

Cited by 14 publications

(10 citation statements)

References 35 publications

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“…Only one study recently investigated SLC46A1 in cases of NTD or cleft lip and palate and failed to show an association (VanderMeer et al, ). Clinical presentations of loss of function mutations of SLC46A1 have been reported in cases of hereditary folate malabsorption, consistent with nullizygous mouse models of Slc46a1 (Diop‐Bove, Jain, Scaglia, & Goldman, ; Salojin et al, ; Shin, Zhao, Fiser, & Goldman, ; Zhao et al, ). SLC25A32 nullizygous mouse embryos exhibited 100% penetrance of neural tube defects, but it is unknown if the defects were compatible with life (Kim, ).…”

Section: Introductionsupporting

confidence: 57%

Mutations in folate transporter genes and risk for human myelomeningocele

Findley

Tenpenny

O'Byrne

et al. 2017

American J of Med Genetics Pt A

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The molecular mechanisms linking folate deficiency and neural tube defect (NTD) risk in offspring remain unclear. Folate transporters (SLC19A1, SLC46A1, SLC25A32, and FOLH1) and folate receptors (FOLR1, FOLR2, and FOLR3) are suggested to play essential roles in transporting folate from maternal intestinal lumen to the developing embryo. Loss of function variants in these genes may affect folate availability and contribute to NTD risk. This study examines whether variants within the folate transporter and receptor genes are associated with an increased risk for myelomeningocele (MM). Exons and their flanking intron sequences of 348 MM subjects were sequenced using the Sanger sequencing method and/or next generation sequencing to identify variants. Frequencies of alleles of single nucleotide polymorphisms (SNPs) in MM subjects were compared to those from ethnically-matched reference populations to evaluate alleles’ associated risk for MM. We identified eight novel variants in SLC19A1 and twelve novel variants in FOLR1, FOLR2, and FOLR3. Pathogenic variants include c.1265delG in SLC19A1 resulting in an early stop codon, four large insertion deletion variants in FOLR3, and a stop_gain variant in FOLR3. No new variants were identified in SLC46A1, SLC25A32, or FOLH1. In SLC19A1, c.80A>G (rs1051266) was not associated with our MM cohort; we did observe a variant allele G frequency of 61.7%, higher than previously reported in other NTD populations. In conclusion, we discovered novel loss of function variants in genes involved in folate transport in MM subjects. Our results support the growing evidence of associations between genes involved in folate transport and susceptibility to NTDs.

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Section: Introductionsupporting

confidence: 57%

Mutations in folate transporter genes and risk for human myelomeningocele

Findley

Tenpenny

O'Byrne

et al. 2017

American J of Med Genetics Pt A

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“…A335D and G338R deep in the 9th TMD (Shin et al, 2011, 2012a) caused a loss of protein; expression of either residue was lost with a positively or negatively charged substitution. The level of expression at the cell membrane for various mutants generally correlated with function.…”

Section: Hereditary Folate Malabsorptionmentioning

confidence: 99%

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

Zhao

Aluri

Goldman

2017

Molecular Aspects of Medicine

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130

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The proton-coupled folate transporter (PCFT) is the mechanism by which folates are absorbed across the apical 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 a basis for the different clinical presentations of HFM and CFD.

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“…However, there can be marked deviations from this scenario in mutated forms of the carrier, as occur in residues identified in subjects with hereditary folate malabsorption (HFM) (36, 37). …”

Section: Folate Absorption In the Proximal Small Intestine: The Apmentioning

confidence: 99%

The Intestinal Absorption of Folates

Visentin

Diop-Bove

Zhao

et al. 2014

Annu. Rev. Physiol.

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163

118

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The properties of intestinal folate absorption were documented decades ago. However, it was only recently that the proton-coupled folate transporter (PCFT) was identified and its critical role in folate transport across the apical brush-border membrane of the proximal small intestine established by the loss-of-function mutations identified in the PCFT gene in subjects with hereditary folate malabsorption and, more recently, by the Pcft-null mouse. This article reviews the current understanding of the properties of PCFT-mediated transport and how they differ from those of the reduced folate carrier. Other processes that contribute to the transport of folates across the enterocyte, along with the contribution of the enterohepatic circulation, are considered. Important unresolved issues are addressed, including the mechanism of intestinal folate absorption in the absence of PCFT and regulation of PCFT gene expression. The impact of a variety of ions, organic molecules, and drugs on PCFT-mediated folate transport is described.

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Functional roles of the A335 and G338 residues of the proton-coupled folate transporter (PCFT-SLC46A1) mutated in hereditary folate malabsorption

Cited by 14 publications

References 35 publications

Mutations in folate transporter genes and risk for human myelomeningocele

Mutations in folate transporter genes and risk for human myelomeningocele

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

The Intestinal Absorption of Folates

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