Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy

• DOI: 10.1016/j.ajhg.2017.03.009
• Publication Date: 2017-04-20T21:33:15Z
• Authors: Myriam Srour; Noriaki Shimokawa; Fadi F. Hamdan; Christina Nassif; Chantal Poulin; Lihadh Al Gazali; Jill A. Rosenfeld; Noriyuki Koibuchi; Guy A. Rouleau; Aisha Al Shamsi; Jacques L. Michaud
• Keywords: Male; 0303 health sciences; Epilepsy; Monosaccharide Transport Proteins; Homozygote; Glucose Transport Proteins, Facilitative; Infant; Pedigree; Young Adult; 03 medical and health sciences; Intellectual Disability; COS Cells; Chlorocebus aethiops; Mutation; Animals; Humans; Female; Child

Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options.