Evaluation of non-coding variation in GLUT1 deficiency
- Author(s)
- Liu, YC; Lee, JW; Bellows, ST; Damiano, JA; Mullen, SA; Berkovic, SF; Bahlo, M; Scheffer, IE; Hildebrand, MS; Clinical, Group;
- Journal Title
- Developental Medicine and Child Neurology
- Publication Type
- Journal Article
- Abstract
- AIM: Loss-of-function mutations in SLC2A1, encoding glucose transporter-1 (GLUT-1), lead to dysfunction of glucose transport across the blood-brain barrier. Ten percent of cases with hypoglycorrhachia (fasting cerebrospinal fluid [CSF] glucose <2.2mmol/L) do not have mutations. We hypothesized that GLUT1 deficiency could be due to non-coding SLC2A1 variants. METHOD: We performed whole exome sequencing of one proband with a GLUT1 phenotype and hypoglycorrhachia negative for SLC2A1 sequencing and copy number variants. We studied a further 55 patients with different epilepsies and low CSF glucose who did not have exonic mutations or copy number variants. We sequenced non-coding promoter and intronic regions. We performed mRNA studies for the recurrent intronic variant. RESULTS: The proband had a de novo splice site mutation five base pairs from the intron-exon boundary. Three of 55 patients had deep intronic SLC2A1 variants, including a recurrent variant in two. The recurrent variant produced less SLC2A1 mRNA transcript. INTERPRETATION: Fasting CSF glucose levels show an age-dependent correlation, which makes the definition of hypoglycorrhachia challenging. Low CSF glucose levels may be associated with pathogenic SLC2A1 mutations including deep intronic SLC2A1 variants. Extending genetic screening to non-coding regions will enable diagnosis of more patients with GLUT1 deficiency, allowing implementation of the ketogenic diet to improve outcomes.
- Publisher
- Wiley
- Research Division(s)
- Population Health And Immunity
- PubMed ID
- 27265003
- Publisher's Version
- https://doi.org/10.1111/dmcn.13163
- NHMRC Grants
- NHMRC/1002098, NHMRC/1054618,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-06-16 12:25:10
Last Modified: 2018-07-11 09:40:12