A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Blood. 2011 May 5;117(18):4895-904. doi: 10.1182/blood-2010-04-279653. Epub 2011 Feb 23.


The human proton coupled folate transporter (PCFT) is involved in low pH-dependent intestinal folate transport. In this report, we describe a new murine model of the hereditary folate malabsorption syndrome that we developed through targeted disruption of the first 3 coding exons of the murine homolog of the PCFT gene. By 4 weeks of age, PCFT-deficient (PCFT(-/-)) mice developed severe macrocytic normochromic anemia and pancytopenia. Immature erythroblasts accumulated in the bone marrow and spleen of PCFT(-/-) mice and failed to differentiate further, showing an increased rate of apoptosis in intermediate erythroblasts and reduced release of reticulocytes. In response to the inefficient hematologic development, the serum of the PCFT(-/-) animals contained elevated concentrations of erythropoietin, soluble transferrin receptor (sCD71), and thrombopoietin. In vivo folate uptake experiments demonstrated a systemic folate deficiency caused by disruption of PCFT-mediated intestinal folate uptake, thus confirming in vivo a critical and nonredundant role of the PCFT protein in intestinal folate transport and erythropoiesis. The PCFT-deficient mouse serves as a model for the hereditary folate malabsorption syndrome and is the most accurate animal model of folate deficiency anemia described to date that closely captures the spectrum of pathology typical of this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Marrow / pathology
  • DNA Primers / genetics
  • Disease Models, Animal
  • Erythropoiesis / genetics
  • Erythropoiesis / physiology
  • Female
  • Folic Acid / metabolism
  • Folic Acid Deficiency / genetics*
  • Folic Acid Deficiency / metabolism*
  • Folic Acid Deficiency / pathology
  • Gene Targeting
  • Humans
  • Intestinal Absorption
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pancytopenia / genetics
  • Pancytopenia / metabolism
  • Pancytopenia / pathology
  • Proton-Coupled Folate Transporter / antagonists & inhibitors*
  • Proton-Coupled Folate Transporter / deficiency
  • Proton-Coupled Folate Transporter / genetics*
  • Spleen / pathology


  • DNA Primers
  • Proton-Coupled Folate Transporter
  • SLC46A1 protein, human
  • Slc46a1 protein, mouse
  • Folic Acid