Molecular Genetics of Hereditary Folate Malabsorption


Hereditary folate malabsorption is a genetic disorder that results in the specific inability to absorb ingested folate in the intestine and to transport serum folate across the blood–brain barrier into the cerebrospinal fluid. Absorption of other vitamins and nutrients is unimpaired. Affected individuals come to medical attention during the first year of life with low serum and cerebrospinal folate levels, megaloblastic anaemia and immunologic and neurologic findings. The disorder is inherited as an autosomal recessive trait and is caused by mutations in the SLC46A1 gene, which encodes the proton‐coupled folate transporter (PCFT). Mutations at SLC46A1 have been identified in over 30 patients with hereditary folate malabsorption. Several of these result in failure to translocate PCFT at the cell membrane; one was shown to encode a protein that was targeted to the cell membrane but did not support folate uptake.

Key Concepts

  • Hereditary folate malabsorption is a rare autosomal recessive genetic disorder.
  • The disorder results in decreased intestinal folate absorption and decreased serum folate levels.
  • It also results in decreased cerebrospinal fluid folate levels owing to decreased folate transport across the blood–brain barrier.
  • Patients have megaloblastic anaemia, immunological deficits and, in some cases, neurological problems.
  • Hereditary folate malabsorption is caused by mutations in the SLC46A1 gene, which encodes the proton‐coupled folate transporter (PCFT).
  • Treatment with parenteral folinic acid corrects both haematological and neurological problems in hereditary folate malabsorption.
  • Study of patients with hereditary folate malabsorption demonstrated that PCFT was the physiological folate transporter in the small intestine.
  • PCFT and folate receptor α are required for folate transport across the blood–brain barrier.

Keywords: megaloblastic anaemia; proton‐coupled folate transporter; SLC46A1; haem carrier protein 1; folinic acid; choroid plexus

Figure 1. Cellular folate metabolism. Cellular folate metabolism involves transfer of one‐carbon units from donor molecules to tetrahydrofolate (THF) to form one‐carbon‐substituted reduced folates and transfer of one‐carbon units from these forms to regenerate THF. Sources of one‐carbon units include breakdown of serine to form 5,10‐methylene‐THF and glycine, catalysed by serine hydroxymethyltransferase (SHMT); breakdown of formiminoglutamate, generated during catabolism of histidine, to form glutamate and 5,10‐methenyl‐THF, catalysed by formiminotransferase/cyclodeaminase (FTCD); and condensation of formate with THF to form 10‐formyl‐THF, catalysed by the formyl‐THF synthetase domain of methylene‐THF dehydrogenase 1 (MTHFD1). On‐carbon‐substituted derivatives of THF are required for several reactions. 5‐Methyl‐THF is required for methylation of homocysteine to form methionine, catalysed by methionine synthase. 5,10‐Methylene‐THF is required for conversion of dUMP to dTMP, catalysed by thymidylate synthase; this reaction generates dihydrofolate (DHF), which is reduced by dihydrofolate reductase (DHFR) to regenerate THF. 10‐Formyl‐THF is required for activity to steps in de novo purine synthesis, conversion of 5‐phosphoribosylglycinamide (GAR) to 5‐N‐glycylglycinamide ribonucleotide (FGAR), catalysed by GAR transformylase; and conversion of 5‐phosphoribosyl‐5‐aminoimidazole‐4‐carboxamide (AICAR) into phosphoribosyl‐5‐formamido‐4‐carboxamide (FAICAR), catalysed by AICAR transformylase. Abbreviation: MTHFR, methylene‐THF reductase.
Figure 2. Structure of PCFT and residues affected by mutations causing inherited folate malabsorption. Amino acid structure of PCFT showing the 12 transmembrane domains (TMD1–TMD12), 5 intracellular loops (IL1–IL5) and 6 extracellular loops (EL1–EL6). Positions of mutations implicated in inherited folate malabsorption are indicated: red indicates a nonsense mutation, green a missense mutation and blue a mutation (insertion or deletion) resulting in a frame shift. One splice site mutation (c. 1082‐1G>A) results in loss of 28 amino acids between positions 362 and 389 (residues shown in yellow). Two different missense mutations affect arginine 113 in IL1 and arginine 376 in TM10, while a missense and a nonsense mutation affect cysteine 66 in EL1.


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Further Reading

Watkins D and Rosenblatt DS (2011) Inherited disorders of folate and cobalamin transport and metabolism. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE and Ballabio A (eds) The Online Metabolic and Molecular Bases of Inherited Disease. DOI: McGraw Hill

Watkins D and Rosenblatt DS (2012) Update and new concepts in vitamin responsive disorders of folate transport and metabolism. Journal of Inherited Metabolic Disease 35: 665–670.

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Watkins, David(Jan 2016) Molecular Genetics of Hereditary Folate Malabsorption. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024325]