Prevalence of a Loss-of-Function Mutation in the Proton-Coupled Folate Transporter Gene (PCFT-SLC46A1) Causing Hereditary Folate Malabsorption in Puerto Rico

Abstract

Objective To determine whether subjects of Puerto Rican heritage are at increased risk for a specific mutation of the proton-coupled folate transporter (PCFT) causing hereditary folate malabsorption (HFM). Study design Three percent of the births in Puerto Rico in 2005, with additional regional oversampling, were screened for the prevalence of the c.1082G>A; p.Y362_G389 del PCFT gene mutation. Six new subjects of Puerto Rican heritage with the clinical diagnosis of HFM were also assessed for this mutation. Results Six subjects of Puerto Rican heritage with the clinical diagnosis of HFM were all homozygous for the c.1082G>A; p.Y362_G389 del PCFT mutation. Three heterozygote carriers were identified from the 1582 newborn samples randomly selected from births in Puerto Rico in 2005. The carrier frequency for the mutated allele was 0.2% island-wide and 6.3% in Villalba. Conclusion These findings are consistent with a common mutation in the PCFT gene causing HFM that has disseminated to Puerto Ricans who have migrated to mainland United States. Because prompt diagnosis and treatment of infants with HFM can prevent the consequences of this disorder, newborn screening should be considered in high-risk populations and physicians should be aware of its prevalence in infants of Puerto Rican ancestry.

Role of Intramuscular Levofolinate Administration in the Treatment of Hereditary Folate Malabsorption: Report of Three Cases

“…Discussion HFM is a rare autosomal recessive condition affecting folate metabolism. So far 37 families have been described worldwide, out of which 30 have as well genetic confirmation (Zhao et al 2007(Zhao et al , 2017Diop-Bove et al 2013;Mahadeo et al 2011;Atabay et al 2010). Our patients were found to have mutations already described in literature as pathogenic (Shin et al 2011;Min et al 2008).…”

Identification and Functional Impact of Homo-oligomers of the Human Proton-coupled Folate Transporter

“…Given the critical roles of hPCFT in intestinal absorption of dietary folates and of mutant hPCFT in HFM (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) and in the selective delivery of cytotoxic antifolates for targeting solid tumors (21, 24 -26), our findings of a functionally important oligomerization for hPCFT are particularly significant. For instance, in HFM, our findings may explain why all HFM patients thus far described have mutations in both pcft gene alleles because loss of a single pcft allele on hPCFT function would probably not be detected (5-15).…”

“…The role of hPCFT in intestinal folate absorption was established by demonstrating loss-of-function mutations in hPCFT in patients with the rare autosomal inherited disorder, hereditary folate malabsorption (HFM) (5). To date, 17 unique hPCFT mutations have been reported in ethnically varied kindreds (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Although proton-coupled, this transporter is also func-tional at more physiologic pH, at which it retains appreciable affinity for pemetrexed (16), a newer antifolate currently approved for treating mesothelioma and non-squamous, nonsmall cell lung cancer (17)(18)(19).…”

The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

“…Loss of hPCFT is associated with hereditary folate malabsorption (HFM) syndrome, a rare autosomal recessive disorder characterized by the onset of macrocytic folate deficiency, anemia, and failure to thrive within the first few months of life (Geller et al, 2002;Qiu et al, 2006;Lasry et al, 2008;Min et al, 2008;Atabay et al, 2010;Mahadeo et al, 2010Mahadeo et al, , 2011Meyer et al, 2010;Shin et al, 2010Shin et al, , 2011Diop-Bove et al, 2013). Other manifestations of HFM include hypoimmunoglobulinemia, developmental delays, gait disorders, peripheral neuropathies, and seizures.…”