Upstream SLC2A1 translation initiation causes GLUT1 deficiency syndrome

• DOI: 10.1038/ejhg.2017.45
• Publication Date: 2017-04-05T10:21:30Z
• Authors: Michèl A Willemsen; Lisenka ELM Vissers; Marcel M Verbeek; Bregje W van Bon; Sinje Geuer; Christian Gilissen; Joerg Klepper; Michael P Kwint; Wilhelmina G Leen; Maartje Pennings; Ron A Wevers; Joris A Veltman; Erik-Jan Kamsteeg
• Keywords: 0301 basic medicine; Glucose Transporter Type 1; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Adolescent; Monosaccharide Transport Proteins; Radboudumc 12: Sensory disorders DCMN: Donders Center for Medical Neuroscience; Neurology - Radboud University Medical Center; Radboud University Medical Center; Codon, Initiator; Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience; Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences; 03 medical and health sciences; Laboratory Medicine - Radboud University Medical Center; Mutation; Humans; Human Genetics - Radboud University Medical Center; Female; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life Sciences; 5' Untranslated Regions; Peptide Chain Initiation, Translational; Cells, Cultured; Carbohydrate Metabolism, Inborn Errors

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder with a complex phenotypic spectrum but simple biomarkers in cerebrospinal fluid. The disorder is caused by impaired glucose transport into the brain resulting from variants in SCL2A1. In 10% of GLUT1DS patients, a genetic diagnosis can not be made. Using whole-genome sequencing, we identified a de novo 5'-UTR variant in SLC2A1, generating a novel translation initiation codon, severely compromising SLC2A1 function. This finding expands our understanding of the disease mechanisms underlying GLUT1DS and encourages further in-depth analysis of SLC2A1 non-coding regions in patients without variants in the coding region.