Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.
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.
Qiu
Andong
A
Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Jansen
Michaela
M
Sakaris
Antoinette
A
Min
Sang Hee
SH
Chattopadhyay
Shrikanta
S
Tsai
Eugenia
E
Sandoval
Claudio
C
Zhao
Rongbao
R
Akabas
Myles H
MH
Goldman
I David
ID
D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004594:Electrophysiology; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D008286:Malabsorption Syndromes / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes; D010375:Pedigree; D058979:Proton-Coupled Folate Transporter; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014981:Xenopus
D026901:Membrane Transport Proteins; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger; C505058:SLC46A1 protein, human; D005492:Folic Acid