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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1147-1152.
Prepublished online as a Blood First Edition Paper on April 19, 2007; DOI 10.1182/blood-2007-02-077099.
 Previous Article | Next Article 
Submitted February 28, 2007
Accepted April 16, 2007
The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption
Rongbao Zhao, Sang Hee Min, Andong Qiu, Antoinette Sakaris, Gary L. Goldberg, Claudio Sandoval, J. Jeffrey Malatack, David S. Rosenblatt, and I. David Goldman*
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, NY
Department of Pediatrics, New York Medical College, Valhalla, NY
Department of Pediatrics, Alfred I. duPont Hospital for Children, Wilmington, DE
Department of Human Genetics, McGill University, Montreal, Canada
* Corresponding author; email: igoldman{at}aecom.yu.edu.
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 one 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 five additional patients. There was no racial, ethnic or gender pattern. Four different homozygous mutations were detected in four patients; two heterozygous mutations were identified in the fifth patient. Mutations involved four of the five exons, all at highly conserved amino acid residues. Four 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 two of the mutated carriers manifested residual function. Folate transport at low pH was markedly impaired in transformed lymphocytes from two 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.
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