SLC46A1 – hereditary folate malabsorption

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by biallelic loss-of-function mutations in the proton-coupled folate transporter gene SLC46A1. Patients typically present in infancy with failure to thrive, macrocytic or normocytic anemia, combined immunodeficiency, and variable neurologic features due to systemic and central nervous system folate deficiency. Early recognition and parenteral folinic acid supplementation can reverse hematologic and immunologic abnormalities.

Genetic evidence supports autosomal recessive inheritance with at least 15 total probands (10 initial PMID:20005757; 5 additional PMID:17446347). Variants include splice‐site mutations (e.g., c.1082-1G>A disrupting exon 3) and frameshift deletions (e.g., c.204_205del (p.Asn68fs)), as well as missense changes that impair transporter stability and function. Segregation in consanguineous families confirms co-segregation of biallelic SLC46A1 variants with HFM phenotypes.

Functional characterization in patient-derived lymphocytes and heterologous expression systems reveals markedly reduced folate transport at low pH for multiple PCFT mutants, driven by defective protein stability, membrane trafficking, and substrate binding (PMID:17446347; PMID:21602279). These studies elucidate critical residues in substrate translocation and confirm loss‐of‐function as the pathogenic mechanism.

No conflicting evidence has been reported: all described SLC46A1 variants consistently abolish PCFT activity and segregate with disease. Early molecular diagnosis enables prompt folinic acid therapy, normalizing blood and cerebrospinal fluid folate levels and preventing irreversible neurologic sequelae.

Key Take-home: Biallelic SLC46A1 mutations cause definitive autosomal recessive hereditary folate malabsorption; genetic testing should be considered in infants with megaloblastic anemia and SCID‐like immunodeficiency, as folinic acid repletion is life-saving.

References

• Clinical immunology (Orlando, Fla.) • 2009 • Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter. PMID:19740703
• Molecular genetics and metabolism • 2010 • A novel PCFT gene mutation (p.Cys66LeufsX99) causing hereditary folate malabsorption. PMID:20005757
• Blood • 2007 • The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. PMID:17446347
• The Journal of biological chemistry • 2011 • Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function. PMID:21602279

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