Background: L-serine plays an essential role in
neuronal development and function. Although a nonessential
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,
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.