The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption

• Published in: Blood Vol. 110; no. 4; pp. 1147 - 1152
• Main Authors: Zhao, Rongbao, Min, Sang Hee, Qiu, Andong, Sakaris, Antoinette, Goldberg, Gary L., Sandoval, Claudio, Malatack, J. Jeffrey, Rosenblatt, David S., Goldman, I. David
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.08.2007; The Americain Society of Hematology; American Society of Hematology
• Series: Hematopoiesis
• Subjects: Amino Acid Sequence; Biological and medical sciences; Blotting, Northern; Blotting, Western; Case-Control Studies; Child, Preschool; DNA Mutational Analysis; Female; Fluorescent Antibody Technique; Folic Acid - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; HeLa Cells; Hematologic and hematopoietic diseases; Hematopoiesis; Heterozygote; Humans; Infant; Intestinal Mucosa - metabolism; Lymphocytes - drug effects; Lymphocytes - metabolism; Malabsorption Syndromes - genetics; Male; Medical sciences; Membrane Transport Proteins - genetics; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Other diseases. Semiology; Pedigree; Polymerase Chain Reaction; Proton-Coupled Folate Transporter; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Sequence specificity; Gene; Hematology; Digestive system; Intestinal malabsorption; Digestive diseases; Intestinal disease; Genetics; Hereditary; Folate
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-02-077099

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by impaired intestinal folate absorption and impaired folate transport into the central nervous system. Recent studies in 1 family revealed that the molecular basis for this disorder is a loss-of-function mutation in the PCFT gene encoding a proton-coupled folate transporter. The current study broadens the understanding of the spectrum of alterations in the PCFT gene associated with HFM in 5 additional patients. There was no racial, ethnic, or sex pattern. A total of 4 different homozygous mutations were detected in 4 patients; 2 heterozygous mutations were identified in the fifth patient. Mutations involved 4 of the 5 exons, all at highly conserved amino acid residues. A total of 4 of the mutated transporters resulted in a complete loss of transport function, primarily due to decreased protein stability and/or defects in membrane trafficking, while 2 of the mutated carriers manifested residual function. Folate transport at low pH was markedly impaired in transformed lymphocytes from 2 patients. These findings further substantiate the role that mutations in PCFT play in the pathogenesis of HFM and will make possible rapid diagnosis and treatment of this disorder in infants, and prenatal diagnosis in families that carry a mutated gene.