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

Damseh, Nadirah; Simonin, Alexandre; Jalas, Chaim; Picoraro, Joseph A; Shaag, Avraham; Cho, Megan T; Yaacov, Barak; Neidich, Julie; Al-Ashhab, Motee; Juusola, Jane; Bale, Sherri; Telegrafi, Aida; Retterer, Kyle; Pappas, John G; Moran, Ellen; Cappell, Joshua; Anyane Yeboa, Kwame; Abu-Libdeh, Bassam; Hediger, Matthias; Chung, Wendy K; ... (2015). Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination. Journal of medical genetics, 52(8), pp. 541-547. BMJ Publishing Group 10.1136/jmedgenet-2015-103104

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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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Simonin, Alexandre and Hediger, Matthias


500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health




BMJ Publishing Group




Kevin Marc Rupp

Date Deposited:

10 Jun 2015 15:55

Last Modified:

26 Jun 2016 02:04

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Molecular genetics Neurology




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