Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome

University of Washington Center for Mendelian Genomics (UW-CMG), Undiagnosed Diseases Network (UDN)

Research output: Contribution to journalArticlepeer-review

Abstract

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine.

Original languageEnglish (US)
Pages (from-to)1046-1053
Number of pages8
JournalAnnals of Clinical and Translational Neurology
Volume10
Issue number6
DOIs
StatePublished - Jun 2023

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Neurology

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