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

  • J Med Genet. 2015 Aug;52(8):541-7. doi: 10.1136/jmedgenet-2015-103104.
Nadirah Damseh  1 ,  Alexandre Simonin  2 ,  Chaim Jalas  3 ,  Joseph A Picoraro  4 ,  Avraham Shaag  5 ,  Megan T Cho  6 ,  Barak Yaacov  5 ,  Julie Neidich  7 ,  Motee Al-Ashhab  1 ,  Jane Juusola  7 ,  Sherri Bale  7 ,  Aida Telegrafi  7 ,  Kyle Retterer  7 ,  John G Pappas  8 ,  Ellen Moran  8 ,  Joshua Cappell  9 ,  Kwame Anyane Yeboa  4 ,  Bassam Abu-Libdeh  1 ,  Matthias A Hediger  2 ,  Wendy K Chung  10 ,  Orly Elpeleg  5 ,  Simon Edvardson  5
Affiliations
  • 1. Department of Pediatrics, Al-Makassed Islamic Hospital, Jerusalem, Israel.
  • 2. NCCR TransCure, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
  • 3. Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA.
  • 4. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
  • 5. Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • 6. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA GeneDx, Gaithersburg, Maryland, USA.
  • 7. GeneDx, Gaithersburg, Maryland, USA.
  • 8. Department of Pediatrics, New York University, New York, New York, USA.
  • 9. Department of Neurology, Columbia University Medical Center, New York, New York, USA.
  • 10. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA Department of Medicine, Columbia University Medical Center, New York, New York, USA.
PMID: 26041762 DOI: 10.1136/jmedgenet-2015-103104
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.

Keywords
Molecular genetics; Neurology.