Identification of an Intestinal Folate Transporter and the Molecular Basis for Hereditary Folate Malabsorption

Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Cell (Impact Factor: 32.24). 01/2007; 127(5):917-28. DOI: 10.1016/j.cell.2006.09.041
Source: PubMed


Folates are essential nutrients that are required for one-carbon biosynthetic and epigenetic processes. While folates are absorbed in the acidic milieu of the upper small intestine, the underlying absorption mechanism has not been defined. We now report the identification of a human proton-coupled, high-affinity folate transporter that recapitulates properties of folate transport and absorption in intestine and in various cell types at low pH. We demonstrate that a loss-of-function mutation in this gene is the molecular basis for hereditary folate malabsorption in a family with this disease. This transporter was previously reported to be a lower-affinity, pH-independent heme carrier protein, HCP1. However, the current study establishes that a major function of this gene product is proton-coupled folate transport required for folate homeostasis in man, and we have thus amended the name to PCFT/HCP1.

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    • "The PCFT plays a key role in intestinal folate absorption and folate transport into the central nervous system (Blount et al. 1997). Loss-of-function mutations in the PCFT gene lead to the rare autosomal recessive disorder, hereditary folate malabsorption, characterized by markedly reduced folate levels in blood and CSF (Blount et al. 1997; Diop- Bove et al. 1993–2014; Geller et al. 2002; Green and Miller 1999; Mahadeo et al. 2010; Qiu et al. 2006; Whitehead 2006; Zhao et al. 2007). Folic acid transport deficiency, another rare congenital metabolic defect, is presumably a recessive disorder, given that it is more prevalent in children of consanguineous matings and may simply be hereditary folate malabsorption (Lanzkowsky et al. 1969). "
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    ABSTRACT: Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46 nmol/L may be sufficient to eradicate CNS disease.
    05/2015; DOI:10.1007/8904_2015_445
    • "Similar to the brush-border membrane, RFC and PCFT are located at the basolateral membrane responsible for trans-membrane transport (Said and Redha, 1987). However, compared with the brush-border membrane transport system, the transport capacity of RFC is lower at the basolateral membrane in the presence of intracellular neutral environment (Said et al., 1987; Said and Redha, 1987) and PCFT is believed to be the major carrier at this level (Qiu et al., 2006). "
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    ABSTRACT: Folate is a vitamin that plays a role as a cofactor and coenzyme in many essential reactions. These reactions are interrelated and any change in folate homeostasis could affect other reactions. With food fortified with folic acid, and use of multivitamin, unmetabolized folic acid (UMFA) has been detected in blood circulation, particularly among older adults. This has raised concern about the potential harmful effect of high folic acid intake and UMFA on health conditions such as cognitive dysfunction and cancer. To examine what is known about folate metabolism and the release of circulating UMFA, the Key Events Dose-Response Framework (KEDRF) was used to review each of the major key events, dose-response characteristics and homeostatic mechanisms of folate metabolism. The intestine, liver and kidneys each play essential roles in regulating body folate homeostasis. But the determining event in folate metabolism leading to the release of UMFA in circulation appears to be the saturation of dihydrofolate reductase in the liver. However, at each of the key events in folate metabolism, limited information is available on threshold, homeostatic regulation and intracellular effects of folic acid. More studies are needed to fill in the knowledge gaps for quantitatively characterizing the dose-effect relationship especially in light of the call for extending folate fortification to other foods.
    Critical Reviews in Food Science and Nutrition 02/2015; DOI:10.1080/10408398.2013.807221 · 5.18 Impact Factor
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    • "W organizmie człowieka foliany ulegają przekształceniu w biologicznie aktywną postać – kwas tetrahydrofoliowy (THF) w dwustopniowej reakcji katalizowanej przez reduktazę dihydrofolianową. THF z pomocą witaminy B6 jest konwertowany do 5,10 – metylotetrahydrofolianu (MTHF), a następnie przez reduktazę MTHF z udziałem witaminy B 2 do 5-metyloTHF [61]. 5-me- tyloTHF jest donorem grupy metylowej w reakcji konwersji homocysteiny do metioniny, katalizowanej przez syntazę metioniny w obecności witaminy B 12 [3] [24]. "
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    ABSTRACT: The number of overweight and obese people is increasing at an alarming rate, especially in the developed and developing countries. Obesity is a major risk factor for diabetes, cardiovascular disease, and cancer, and in consequence for premature death. The development of obesity results from the interplay of both genetic and environmental factors, which include sedentary life style and abnormal eating habits. In the past few years a number of events accompanying obesity, affecting expression of genes which are not directly connected with the DNA base sequence (e.g. epigenetic changes), have been described. Epigenetic processes include DNA methylation, histone modifications such as acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, as well as non-coding micro-RNA (miRNA) synthesis. In this review, the known changes in the profile of DNA methylation as a factor affecting obesity and its complications are described.
    Postępy Higieny i Medycyny Doświadczalnej (Advances in Hygiene and Experimental Medicine) 11/2014; 68:1383-1391. · 0.57 Impact Factor
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