Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination

J Med Genet. 2015 Aug;52(8):541-7. doi: 10.1136/jmedgenet-2015-103104. Epub 2015 Jun 3.


Background: L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1.

Methods and results: Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1.

Conclusions: The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

Keywords: Molecular genetics; Neurology.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Transport System ASC / genetics*
  • Biological Transport / genetics
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Developmental Disabilities / genetics*
  • Female
  • Genetic Carrier Screening
  • HEK293 Cells
  • Heterozygote
  • Humans
  • Male
  • Microcephaly / genetics*
  • Myelin Sheath / metabolism
  • Pedigree
  • Serine / metabolism


  • Amino Acid Transport System ASC
  • SLC1A4 protein, human
  • Serine