RT Journal Article
SR Electronic
T1 Mutations in <em>SLC1A4</em>, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 541
OP 547
DO 10.1136/jmedgenet-2015-103104
VO 52
IS 8
A1 Nadirah Damseh
A1 Alexandre Simonin
A1 Chaim Jalas
A1 Joseph A Picoraro
A1 Avraham Shaag
A1 Megan T Cho
A1 Barak Yaacov
A1 Julie Neidich
A1 Motee Al-Ashhab
A1 Jane Juusola
A1 Sherri Bale
A1 Aida Telegrafi
A1 Kyle Retterer
A1 John G Pappas
A1 Ellen Moran
A1 Joshua Cappell
A1 Kwame Anyane Yeboa
A1 Bassam Abu-Libdeh
A1 Matthias A Hediger
A1 Wendy K Chung
A1 Orly Elpeleg
A1 Simon Edvardson
YR 2015
UL http://jmg.bmj.com/content/52/8/541.abstract
AB 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.