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

Abstract

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 wellconserved 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 ¼ 0.013) and 33% (p ¼ 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.Glucose is the major energy fuel of the central nervous system. However, its availability is restricted given the selective permeability of the blood brain barrier (BBB) and the relative lack of carbohydrate stores in the brain. Thus, glucose transport across the BBB and into neural cells is critical for cerebral physiologic function and energy metabolism (for a review, see Chen et al. 1 ). GLUT1 is the key regulator of glucose across the BBB. 1 The importance of this process is illustrated by the observation that dominant mutations in SLC2A1 (OMIM: 138140), which encodes GLUT1, cause epilepsy with variable degrees of intellectual disability (ID) and/or movement disorder. 2 Once glucose enters the brain's extracellular space, it is taken up by different cerebral cells through various glucose transporters, which are expressed in developmentally and celltype-specific manners. Whether disruption of these neural glucose transporters also causes neurodevelopment disorders remains unknown.We report on four affected children from two unrelated consanguineous families with moderate to severe ID associated with epilepsy and variable neuropsychiatric features. Using whole-exome sequencing, we identified homozygous missense variants in SLC45A1 (OMIM: 605763), which codes for a neuronal glucose transporter that is predominantly expressed in the developing and adult brain. 3 Functional studies indicate that the identified variants reduce the activity of the protein, thus implicating SLC45A1 dysfunction in the etiology of ID a...

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins

“…It is a protein-coding gene and associated with intellectual developmental disorder with neuropsychiatric features and autosomal recessive non-syndromic intellectual disability ( https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC45A1 ). Srour et al ( 2017 ) studied homozygous missense variants in SLC45A1 on four affected children from two unrelated consanguineous families with moderate to severe intellectual disability associated with epilepsy and variable neuropsychiatric features. They concluded that autosomal-recessive mutations in SLC45A1 result in intellectual disability, movement disorder, and epilepsy.…”

Individualizing Treatment Approaches for Epileptic Patients with Glucose Transporter Type1 (GLUT-1) Deficiency

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