title: Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors.forename: Nadirah
authors.initials: N
authors.lastname: Damseh
authors.affiliation: NCCR TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Simonin
authors.affiliation: Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA.
authors.forename: Chaim
authors.initials: C
authors.lastname: Jalas
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Picoraro
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Barak
authors.initials: B
authors.lastname: Yaacov
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Neidich
authors.affiliation: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors.forename: Motee
authors.initials: M
authors.lastname: Al-Ashhab
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Aida
authors.initials: A
authors.lastname: Telegrafi
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Retterer
authors.affiliation: Department of Pediatrics, New York University, New York, New York, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Pappas
authors.affiliation: Department of Pediatrics, New York University, New York, New York, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Moran
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Cappell
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Kwame
authors.initials: K
authors.lastname: Anyane Yeboa
authors.affiliation: Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
authors.forename: Bassam
authors.initials: B
authors.lastname: Abu-Libdeh
authors.affiliation: NCCR TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Hediger
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
mesh_terms: D000293:Adolescent; D026962:Amino Acid Transport System ASC / Q000235:genetics*; D001692:Biological Transport / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009186:Myelin Sheath / Q000378:metabolism; D010375:Pedigree; D012694:Serine / Q000378:metabolism
chemical_list: D026962:Amino Acid Transport System ASC; C498848:SLC1A4 protein, human; D012694:Serine
keywords: Molecular genetics; Neurology