title: SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum.
abstract: Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel.|The Pinchas Borenstein Talpiot Medical Leadership Program, Ramat Gan, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Heimer
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Marek-Yagel
authors.affiliation: Cancer Research Center, Pediatric Hemato/oncology Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Eyal
authors.affiliation: Cancer Research Center, Pediatric Hemato/oncology Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Barel
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Oz Levi
authors.affiliation: Diagnostic Imaging Unit, The Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: C
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Ruzzo
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Ganelin-Cohen
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Lancet
authors.affiliation: Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.|The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Pras
authors.affiliation: Cancer Research Center, Pediatric Hemato/oncology Unit, Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center, Ramat Gan, Israel.|The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Rechavi
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel.|The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Nissenkorn
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel.|The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Institute for Genomic Medicine, Columbia University Medical School, Columbia University Medical Center, New York, NY, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Goldstein
authors.affiliation: Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Ramat Gan, Israel.|The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Ben Zeev
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D026962:Amino Acid Transport System ASC / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D008831:Microcephaly / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009128:Muscle Spasticity / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D016415:Sequence Alignment
chemical_list: D026962:Amino Acid Transport System ASC; C498848:SLC1A4 protein, human
keywords: ASCT1; SLC1A4; acquired microcephaly; cerebral atrophy; mental retardation; seizures; serine; spastic quadriparesis; thin corpus callosum