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Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination
  1. Nadirah Damseh1,
  2. Alexandre Simonin2,
  3. Chaim Jalas3,
  4. Joseph A Picoraro4,
  5. Avraham Shaag5,
  6. Megan T Cho4,6,
  7. Barak Yaacov5,
  8. Julie Neidich6,
  9. Motee Al-Ashhab1,
  10. Jane Juusola6,
  11. Sherri Bale6,
  12. Aida Telegrafi6,
  13. Kyle Retterer6,
  14. John G Pappas7,
  15. Ellen Moran7,
  16. Joshua Cappell8,
  17. Kwame Anyane Yeboa4,
  18. Bassam Abu-Libdeh1,
  19. Matthias A Hediger2,
  20. Wendy K Chung4,9,
  21. Orly Elpeleg5,
  22. Simon Edvardson5
  1. 1Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel
  2. 2NCCR TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland
  3. 3Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA
  4. 4Department of Pediatrics, Columbia University Medical Center, New York, New York, USA
  5. 5Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  6. 6GeneDx, Gaithersburg, Maryland, USA
  7. 7Department of Pediatrics, New York University, New York, New York, USA
  8. 8Department of Neurology, Columbia University Medical Center, New York, New York, USA
  9. 9Department of Medicine, Columbia University Medical Center, New York, New York, USA
  1. Correspondence to Professor Orly Elpeleg, Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Elpeleg{at}Hadassah.org.il and Wendy Chung, Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; wkc15{at}cumc.columbia.edu

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.

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.

  • Neurology
  • Molecular genetics

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