Alternative titles; symbols
HGNC Approved Gene Symbol: SLC2A1
SNOMEDCT: 715564000, 724072002;
Cytogenetic location: 1p34.2 Genomic coordinates (GRCh38): 1:42,925,353-42,958,868 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.2 | {Epilepsy, idiopathic generalized, susceptibility to, 12} | 614847 | Autosomal dominant | 3 |
| Dystonia 9 | 601042 | Autosomal dominant | 3 | |
| GLUT1 deficiency syndrome 1, infantile onset, severe | 606777 | Autosomal dominant; Autosomal recessive | 3 | |
| GLUT1 deficiency syndrome 2, childhood onset | 612126 | Autosomal dominant | 3 | |
| Stomatin-deficient cryohydrocytosis with neurologic defects | 608885 | Autosomal dominant | 3 |
The SLC2A1 gene encodes the major glucose transporter in brain, placenta, and erythrocytes (Baroni et al., 1992). SLC2A1 also transports dehydroascorbic acid (the oxidized form of vitamin C) (Agus et al., 1997) and functions as a receptor for human T-cell leukemia virus (HTLV) (Manel et al., 2003).
Mueckler et al. (1985) isolated a cDNA corresponding to human GLUT1 from human HepG2 hepatoma cells. The deduced amino acid sequence indicates that this protein lacks a signal sequence and possesses 12 potential membrane-spanning domains. The amino terminus, carboxyl terminus, and a highly hydrophilic domain in the center of the protein ware all predicted to lie on the cytoplasmic face of the cell.
Wang et al. (2000) stated that the SLC2A1 gene encodes a 492-amino acid protein with 97 to 98% identity between human, rat, rabbit, and pig sequences.
Wang et al. (2000) stated the SLC2A1 gene contains 10 exons and spans approximately 35 kb.
Crystal Structure
Deng et al. (2014) reported the crystal structure of human GLUT1 at 3.2-angstrom resolution. The full-length protein, which has a canonical major facilitator superfamily fold, is captured in an inward-open conformation. This structure allows accurate mapping and potential mechanistic interpretation of disease-associated mutations in GLUT1. Structure-based analysis of these mutations provides insight into the alternating access mechanism of GLUT1 and other members of the sugar porter subfamily. Structural comparison of the uniporter GLUT1 with its bacterial homolog XylE, a proton-coupled xylose symporter, allows examination of the transport mechanisms of both passive facilitators and active transporters.
Wang et al. (2005) stated that the SLC2A1 gene maps to chromosome 1p34.2.
Shows et al. (1987) mapped the SLC2A1 gene to chromosome 1p35-p31.3 by in situ hybridization and by Southern blot analysis of somatic cell hybrids. They concluded that the most likely location of SLC2A1 is in 1p33.
Ardinger et al. (1987) found linkage between Rh and a DNA polymorphism for GLUT (theta = 0.21; lod = 3.54). Multipoint analysis indicated that the order of the loci is probably RH--3--ALPL--12--GLUT--23--PGM1, with the interlocus intervals as percent recombination in males (female rate about 2.8 times the male rate). Xiang et al. (1987) described a RFLP of the GLUT locus.
The high metabolic requirements of the mammalian central nervous system require specialized structures for the facilitated transport of nutrients across the blood-brain barrier. The facilitative glucose transporter GLUT1 is expressed on endothelial cells at the blood-brain barrier and is responsible for glucose entry into the brain (Agus et al., 1997). Stereo-specific high-capacity carriers, including those that recognize glucose, are key components of this barrier, which also protects the brain against noxious substances.
Agus et al. (1997) provided evidence that GLUT1 also transports dehydroascorbic acid (the oxidized form of vitamin C) into the brain. Vitamin C concentrations in the brain exceed those in blood by 10 fold. In both tissues, the vitamin is present primarily in the reduced form, ascorbic acid. Agus et al. (1997) showed that ascorbic acid is not able to cross the blood-brain barrier; in contrast, dehydroascorbic acid readily enters the brain and is retained in the brain tissue in the form of ascorbic acid. Transport of dehydroascorbic acid into the brain is inhibited by D-glucose, but not by L-glucose. Thus, transport of dehydroascorbic acid by GLUT1 is a mechanism by which the brain acquires vitamin C. The studies of Agus et al. (1997) pointed to the oxidation of ascorbic acid as a potentially important regulatory step in accumulation of the vitamin by the brain. These results have implications for increasing antioxidant potential in the central nervous system.
Lazar et al. (1999) studied the expression of 4 thyroid-specific genes (sodium-iodide symporter (NIS, or SLC5A5; 601843), thyroid peroxidase (TPO; 606765), thyroglobulin (TG; 188450), and thyroid-stimulating hormone receptor (TSHR; 603372)) as well as the gene encoding GLUT1 in 90 human thyroid tissues. mRNAs were extracted from 43 thyroid carcinomas (38 papillary and 5 follicular), 24 cold adenomas, 5 Graves thyroid tissues, 8 toxic adenomas, and 5 hyperplastic thyroid tissues; 5 normal thyroid tissues were used as reference. Expression of the GLUT1 gene was increased in 1 of 24 (4%) adenomas and in 8 of 43 (19%) thyroid carcinomas. 3 patients with normal GLUT1 expression had 131-I uptake in metastases, whereas the other 3 patients with increased GLUT1 gene expression had no detectable 131-I uptake. The authors concluded that an increased expression of GLUT1 in some malignant tumors may suggest a role for glucose-derivative tracers to detect in vivo thyroid cancer metastases by positron-emission tomography scanning.
Translational repression of GLUT1 in glioblastoma multiforme (GBM; 137800) is mediated by a specific RNA-binding protein that interacts with an AU-rich response element in the 3-prime UTR of the GLUT1 transcript. Hamilton et al. (1999) showed that HNRNPA2 (600124) and HNRNPL (603083) bound the 3-prime UTR of GLUT1 mRNA. Induction of brain ischemia in rats or hypoglycemic stress in 293 cells increased GLUT1 expression via mRNA stability. Polysomes isolated from ischemic rat brains or hypoglycemic 293 cells showed loss of HNRNPA2 and HNRNPL, suggesting that reduced levels of these RNA-binding proteins results in GLUT1 mRNA stability.
Manel et al. (2003) showed that the receptor-binding domains of the HTLV-1 and -2 envelope glycoproteins inhibited glucose transport by interacting with GLUT1, the ubiquitous vertebrate glucose transporter. Receptor binding and HTLV envelope-driven infection were selectively inhibited when glucose transport or GLUT1 expression were blocked by cytochalasin B or siRNAs, respectively. Furthermore, ectopic expression of GLUT1, but not the related transporter GLUT3 (138170), restored HTLV infection abrogated by either GLUT1 siRNAs or interfering HTLV envelope glycoproteins. Manel et al. (2003) concluded that GLUT1 is a receptor for HTLV and suggested that perturbations in glucose metabolism resulting from interactions of HTLV envelope glycoproteins with GLUT1 are likely to contribute to HTLV-associated disorders.
Roach and Plomann (2007) found that overexpression of PACSIN3 (606513) elevated glucose transport by increasing the content of GLUT1 in the plasma membrane, despite the total amount of cellular GLUT1 remaining unchanged.
Montel-Hagen et al. (2008) stated that, of all human cell lineages, erythrocytes express the highest level of GLUT1, with more than 200,000 molecules per cell. They showed that GLUT1 preferentially transported L-dehydroascorbic acid (DHA) rather than glucose in human erythrocytes. This switch from glucose to DHA was associated with induction of stomatin (EPB72; 133090), an integral erythrocyte membrane protein. Accordingly, in a patient with overhydrated hereditary stomatocytosis (185000), a disorder characterized by low stomatin levels, DHA transport was decreased by 50%, while glucose uptake was significantly increased. Montel-Hagen et al. (2008) found that erythrocyte-specific GLUT1 expression and DHA transport are specific traits of vitamin C-deficient mammalian species, encompassing only higher primates, guinea pigs, and fruit bats. Adult mouse erythrocytes expressed Glut4 rather than Glut1 and did not transport DHA. Montel-Hagen et al. (2008) concluded that induction of GLUT1 and stomatin during erythroid differentiation is a compensatory mechanism in mammals unable to synthesize vitamin C.
By studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS (190070) or BRAF (164757) genes, Yun et al. (2009) found that GLUT1 was 1 of 3 genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wildtype KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Yun et al. (2009) concluded that, taken together, these data suggested that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors.
Lee et al. (2015) identified serine-226 (S226) in GLUT1 as a protein kinase C (PKC) phosphorylation site. In vitro kinase studies, mass spectrometry, and phosphospecific antibody studies showed that phosphorylation of S226 was required for enhanced cell surface localization of GLUT1 and for a rapid increase in glucose uptake under induced conditions in endothelial cells. Several naturally occurring GLUT1 mutations (see, e.g., R223P, 138140.0020) impaired the phosphorylation of S226, resulting in decreased responsiveness of surface relocalization of GLUT1 despite the presence of endogenous GLUT1.
Role in Diabetes
Insulin increases glucose uptake in responsive cells by inducing the rapid translocation of glucose transporters from an intracellular storage pool to the plasma membrane. Li et al. (1988) demonstrated a significantly increased frequency of the X1 allele (the 6.2 kb fragment recognized by the human glucose transporter cDNA) among 89 patients with noninsulin-dependent diabetes mellitus (NIDDM; 125853) from 3 different ethnic populations. They suggested that the observed association may reflect linkage of the X1 allele to a putative diabetogenic locus on chromosome 1; they hypothesized that the glucose transporter gene itself may be a major genetic determinant for noninsulin-dependent diabetes mellitus. Baroni et al. (1992) extended the data suggesting an association between polymorphic markers at the GLUT1 locus and NIDDM in the Italian population studied.
Shepherd and Kahn (1999) discussed in detail the role of glucose transporters in insulin action and the implications for insulin resistance and diabetes mellitus. In their Table 1, they presented 5 forms of GLUT (GLUT1-5) and gave the approximate K(m) for glucose and the tissue distribution and characteristics of each. They pointed out that GLUT4 (138190) is the main insulin-responsive glucose transporter, being located primarily in muscle cells and adipocytes. The role of GLUT4 in the mechanism of effectiveness of drug therapy for diabetes was reviewed.
Lohmueller et al. (2003) performed a metaanalysis of 301 published genetic association studies covering 25 different reported associations. For 8 of the associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. One of these 8 was the association between type II diabetes and an XbaI RFLP (6.2-kb allele) of the SLC2A1 gene, as first reported by Li et al. (1988).
GLUT1 Deficiency Syndrome 1
In patients with a transport defect of glucose across the blood-brain barrier, consistent with GLUT1 deficiency syndrome-1 (GLUT1DS1; 606777), Seidner et al. (1998) identified heterozygous mutations in the SLC2A1 gene (138140.0001-138140.0003). Two of the patients had been reported by De Vivo et al. (1991).
Klepper et al. (2001) reported a father and 2 children from separate marriages who were affected by GLUT1 deficiency, and confirmed autosomal dominant transmission by identifying a heterozygous mutation in the GLUT1 gene (G91D; 138140.0006). The father developed generalized tonic-clonic seizures and myoclonic seizures at age 3 years. As an adult, he had mild mental retardation, depression, and migraine. One daughter had mild spastic diplegia at age 9 months and showed developmental delay over the next 2 years. At age 3, she developed complex partial seizures. At age 10, she had moderate mental retardation, cerebellar ataxia, and mild pyramidal signs of the legs. The second daughter showed developmental delay, spastic diplegia, and generalized tonic-clonic seizures at age 2 years. Physical exam at age 22 years revealed moderate mental retardation, cerebellar ataxia, and spastic tetraplegia that predominantly involved the legs. The 2 daughters both had hypoglycorrhachia.
Among 16 patients with GLUT1 deficiency, Wang et al. (2005) identified 16 different mutations in the SLC2A1 gene; 14 of the mutations were novel.
Stomatin-Deficient Cryohydrocytosis with Neurologic Defects
In 2 unrelated patients with stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN; 608885), originally reported by Fricke et al. (2004), Flatt et al. (2011) identified 2 different heterozygous mutations in the SLC2A1 gene (138140.0023 and 138140.0024). In vitro functional expression assays in Xenopus oocytes showed that the mutant proteins did not transport glucose and leaked cations.
In an infant with SDCHCN, Bawazir et al. (2012) identified a de novo heterozygous mutation in the SLC2A1 gene (138140.0024); the same mutation was identified in 1 of the patients reported by Flatt et al. (2011). Western blot analysis showed that GLUT1 was expressed normally at the red cell membrane, whereas stomatin (STOM; 133090) levels were decreased. The authors suggested that the multisystem pathology in this disorder likely reflects a combination of glucose transport deficiency at the blood-brain barrier, resulting in neurologic deficits consistent with GLUT1 deficiency syndrome-1 (GLUT1DS1; 606777), and red cell membrane cation defects, resulting in pseudohyperkalemia and red cell hemolysis.
GLUT1 Deficiency Syndrome 2
Overweg-Plandsoen et al. (2003) reported a 6-year-old boy with GLUT1 deficiency who had delayed psychomotor development, moderate mental retardation, horizontal nystagmus, dysarthria, limb ataxia, hyperreflexia, and dystonic posturing of the limbs, consistent with GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126). He had never had seizures. The motor activity and coordination fluctuated throughout the day, which was unrelated to food intake. Laboratory studies showed hypoglycorrhachia and low CSF lactate. Genetic analysis identified a de novo heterozygous mutation in the GLUT1 gene (N34I; 138140.0011). A ketogenic diet helped with the motor symptoms.
In affected members of 3 unrelated families with paroxysmal exercise-induced dyskinesias (PED) consistent with GLUT1DS2, Weber et al. (2008) identified 3 different heterozygous mutations in the SLC2A1 gene (138140.0008-138140.0010). The phenotype was characterized by childhood onset of paroxysmal exertion-induced dyskinesias. One family also had hematologic abnormalities consistent with hemolytic anemia. Based on these findings and brain imaging studies, Weber et al. (2008) concluded that the dyskinesias resulted from an exertion-induced energy deficit causing episodic dysfunction in the basal ganglia. The hemolysis observed in 1 family was demonstrated in vitro in Xenopus oocytes and human erythrocytes to result from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.
In affected members of a large Belgian family segregating PED and epilepsy, Suls et al. (2008) identified a heterozygous missense mutation in the GLUT1 gene (S95I; 138140.0012).
Schneider et al. (2009) identified 2 different de novo heterozygous mutations in the GLUT1 gene (see, e.g., 138140.0015) in 2 of 10 unrelated Caucasian patients with paroxysmal exercise-induced dyskinesias. One of the patients had childhood onset of absence epilepsy.
Susceptibility to Idiopathic Generalized Epilepsy 12
Suls et al. (2009) identified heterozygous mutations (see, e.g., 138140.0020) in the SLC2A1 gene in 4 (12%) of 34 patients with early-onset absence epilepsy before age 4 years (EIG12; 614847). CSF glucose levels were not available from any of the patients. One of the patients had no additional abnormalities and normal development. However, clinical review of these patients after diagnosis showed that 3 had mild to moderate mental retardation, 2 had mild ataxia, and 1 had myoclonus and exercise-induced paroxysmal dyskinesia. None had microcephaly. Two patients inherited missense mutations from parents with later-onset absence epilepsy. The findings further expanded the phenotype associated with SLC2A1 mutations, and suggested that patients with onset of absence seizures before age 4 years in particular should be screened for mutations in this gene.
In 8 affected members of an Italian family with idiopathic generalized epilepsy-12 manifest mainly as childhood-onset absence seizures, Striano et al. (2012) identified a heterozygous mutation in the SLC2A1 gene (R232C; 138140.0019). The mutation was also found in 4 healthy adult family members, yielding a reduced penetrance of 67%. In vitro functional studies showed that the mutant protein was expressed at the cell surface but had mildly decreased glucose uptake (70%) compared to wildtype. The mutation was found in 1 of 95 families with EIG. These findings suggested that GLUT1 deficiency is a rare cause of typical EIG, and also expanded the phenotypic spectrum associated with mutations in the SLC2A1 gene.
Dystonia 9
In affected members of the family with autosomal dominant dystonia-9 (DYT9; 601042) originally reported by Auburger et al. (1996), Weber et al. (2011) identified a heterozygous mutation in the SLC2A1 gene (R232C; 138140.0018). Two Australian brothers with the disorder carried a different heterozygous mutation (R126C; 138140.0014). The disorder was characterized by childhood onset of paroxysmal choreoathetosis and progressive spastic paraplegia. Most showed some degree of cognitive impairment. Other variable features included seizures, migraine headaches, and ataxia.
Variant Function
Using proteomics screening to investigate the effect of missense mutations in intrinsically disordered regions (IDRs) of proteins on protein-protein interactions, Meyer et al. (2018) identified 3 mutations in cytosolic tails of 3 different transmembrane proteins that create dileucine motifs and lead to increased binding of clathrin. The authors selected the P485L mutation in GLUT1, which had been identified in GLUT1 deficiency, to characterize functionally. Expression analysis in HEK cells showed that the P485L mutation caused mislocalization of GLUT1 from the plasma membrane to endocytic compartments. Proximity-dependent biotin identification revealed that the mutant protein colocalized with proteins involved in membrane trafficking, clathrin-mediated endocytosis, and post-Golgi trafficking, in particular with all subunits of adaptor proteins AP1 (see 607291), AP2 (see 601024), and AP3 (see 602416), which bind directly to both dileucine motifs and clathrin to mediate cellular transport. Pull-down assay demonstrated that mutant GLUT1 interacted with APs via its cytosolic tail, providing a molecular explanation for mistrafficking of clathrin by a glucose transporter. Further analysis revealed that the interaction between GLUT1 and AP2 also contributed to the internalization of GLUT1 from the plasma membrane, as the loss of AP2 rescued the mislocalization of mutated GLUT1 and increased glucose uptake by mutant GLUT1. In fibroblasts derived from a GLUT1-deficient patient harboring the P485L mutation reprogrammed into induced pluripotent stem cells, the mislocalization observed in HEK cells was recapitulated, validating the in vitro results. Moreover, knocking in the P485L mutation in mice resulted in the death of homozygous mutant pups immediately after birth, and histologic analysis in endothelial cells of the blood brain barrier from mutant mouse embryos found that the P485L mutation reduced GLUT1 levels in the plasma membrane in vivo.
In mouse preimplantation embryos, Moley et al. (1998) found that glucose uptake was significantly lowered in embryos from diabetic mice compared to control mice. Diabetic embryos had significantly decreased levels of Glut1 mRNA and protein levels, indicating a decrease in glucose utilization directly related to a decrease in glucose transport. Chi et al. (2000) found that decreased Glut1 expression and function resulted in a high rate of apoptosis at the murine blastocyst stage via a Bax (600040)-dependent apoptotic cascade. The findings suggested that maternal hyperglycemia induces a cell death signal by decreasing glucose transport. This results in a loss of key progenitor cells during the blastocyst stage, which may manifest as embryonic resorption or malformation. In transgenic mice generated using antisense Glut1, Heilig et al. (2003) found reduction of glucose uptake, by 50% in presumed heterozygotes and 95% in presumed homozygotes, as well as developmental malformations associated with maternal diabetes, including intrauterine growth retardation, anencephaly, microphthalmia, and caudal regression syndrome, an impaired development of the hind portion of the embryo. Macrosomia was not observed. The homozygous Glut1 mutant phenotype was lethal during gestation, and reduced embryonic Glut1 was associated with apoptosis. Heilig et al. (2003) suggested that GLUT1 deficiency causes a decrease in embryonic glucose uptake and apoptosis, which may be involved in diabetic embryopathy.
Wang et al. (2006) found that mice with targeted heterozygous disruption of the Glut1 gene developed spontaneous epileptiform discharges, impaired motor activity, incoordination, hypoglycorrhachia, decreased brain weight (microencephaly), decreased brain glucose uptake, and decreased expression of Glut1 in the brain (66% of controls). Homozygous mutant mice were embryonic lethal. Wang et al. (2006) suggested that Glut1 +/- mice mimics the classic human presentation of GLUT1 deficiency and can be used as an animal model to examine the pathophysiology of the disorder in vivo.
In zebrafish, Zheng et al. (2010) found that knockdown of Glut1 resulted in impaired development of cerebral endothelial cells, disruption of the junctional barrier of the blood-brain barrier, impaired cerebral circulation, and vasogenic brain edema. The authors concluded that Glut1 plays a role in the development of cerebral endothelial cells with properties of the blood-brain barrier.
The human T-cell leukemia (lymphoma) virus HTLV-1 was first isolated in the United States in cases of adult T-cell lymphoma and leukemia (Poiesz et al. (1980, 1981); Gallo et al., 1982). Subsequently it was found associated with T-cell leukemia in patients in Japan and the West Indies by detection of HTLV-specific antibodies in the serum. Sarin et al. (1983) found a Japanese family in which one member, a 21-year-old college student, had acute T-cell leukemia and his mother had morphologically abnormal lymphocytes with convoluted nuclei typically found in T-cell leukemia or lymphoma patients. Other family members, with the exception of the patient's sister, either had HTLV-related serum antibodies or expressed HTLV-related antigens (or both) in cultured T cells and expressed HTLV-1 particles. Acute T-cell leukemia is relatively frequent in natives of Kyushu and Shikoku in southwestern Japan. The family described by Sarin et al. (1983) was from Honshu in northwestern Japan and had no family ties to the 2 endemic areas. No consistent cytogenetic abnormality was found.
HTLV-1 and HTLV-2 can infect many types of human cells in vitro. Blocking assays of syncytium formation and of vesicular stomatitis virus pseudotypes bearing the envelope glycoproteins of HTLV show that these 2 viruses utilize the same cell surface receptor. Since the above-mentioned pseudotypes have a low plating efficiency on murine cells compared to human cells, Sommerfelt et al. (1988) were able to use human-mouse somatic cell hybrids to determine which human chromosome confers susceptibility to HTLV infection. The only human chromosome common to all susceptible cell hybrids was chromosome 17; the receptor gene was further localized to 17cen-qter. The receptor is probably a previously unidentified surface antigen because antibodies to nonsurface antigens did not block the HTLV receptor. It may be significant that in vivo HTLV-1 appears to integrate preferentially into chromosomes 7 and 17 (Seiki et al., 1984) and that rearrangements involving these chromosomes have been noted in adult T-cell leukemia cells. Furthermore, Hinrichs et al. (1987) found that transgenic mice expressing the tat gene of HTLV-1 develop a syndrome resembling neurofibromatosis (162200), a disorder that has been localized to human chromosome 17cen-q21. The only other retroviral receptor molecule unequivocally identified was the CD4 leukocyte antigen, which is used by HIV viruses involved in AIDS.
HTLV-1 is etiologically associated with adult T-cell leukemia/lymphoma and tropical spastic paraparesis (see 159580), while HTLV-2 is associated with T-cell hairy cell leukemia (HCL) (Rosenblatt et al., 1986). Ratner et al. (1990) described the cases of an adult black brother and sister who developed adult T-cell leukemia/lymphoma resulting from infection from HTLV-1. Both had lived almost exclusively in the area of St. Louis, Missouri.
Based on the fact that HTLV infection induces syncytium formation of infected cells as a result of interaction between the viral envelope and viral receptor, Tajima et al. (1997) performed a sensitive biologic assay using the recombinant vaccinia expression system. From the induced syncytium pattern of somatic hybrid cell lines with different deletions involving chromosome 17, Tajima et al. (1997) concluded that the HTLVR gene resides on 17q21-q23.
Familial hairy cell leukemia occurs rarely, and HCL occurring in association with other hematologic malignancies is even rarer. Makower et al. (1998) described a mother and son with HCL, and an HCL patient whose aunt developed Hodgkin disease (236000). This was said to be the first reported familial association of HCL with Hodgkin disease.
In a patient originally reported by De Vivo et al. (1991) with severe manifestations related to a demonstrable defect in glucose transport across the blood-brain barrier (GLUT1DS1; 606777), Seidner et al. (1998) identified a heterozygous deletion of the GLUT1 gene. The deletion appeared to be a de novo mutation.
Wang et al. (2000) identified 1 patient who was hemizygous for the GLUT1 gene.
In a patient with severe clinical consequences of a defect in the transport of glucose across the blood-brain barrier (GLUT1DS1; 606777), Seidner et al. (1998) identified a heterozygous 1545A-T transversion in the SLC2A1 gene, resulting in a lys456-to-ter (K456X) substitution.
In a patient originally reported by De Vivo et al. (1991) with severe clinical consequences of a defect in the transport of glucose across the blood-brain barrier (GLUT1DS1; 606777), Seidner et al. (1998) identified a heterozygous 1526C-A transversion in the SLC2A1 gene, resulting in a tyr449-to-ter (Y449X) substitution.
In a patient with blood-brain barrier glucose transport defect (see 606777), Wang et al. (2000) identified compound heterozygosity for 2 mutations in the SLC2A1 gene: a 945A-G transition in exon 5, resulting in a lys256-to-val (K256V) substitution on the maternally derived allele, and a 556G-T transversion in exon 4, resulting in an arg126-to-leu (R126L; 138140.0005) substitution on the paternally derived allele. In addition to having no noticeable symptoms of GLUT1 deficiency syndrome, the mother had no defect in erythrocyte glucose uptake in vitro. Wang et al. (2000) raised the possibility of a synergistic effect of these 2 mutations when present in compound heterozygous state.
Rotstein et al. (2010) provided further details of the patient with autosomal recessive GLUT1 deficiency syndrome reported by Wang et al. (2000). He developed recurrent limb stiffening and cyanosis at age 6 weeks. Seizures included tonic eye deviation, staring spells, myoclonic jerks, and prolonged and refractory generalized tonic-clonic seizures. He had delayed psychomotor development and progressive microcephaly. CSF showed hypoglycorrhachia. A ketogenic diet was helpful, but his developmental quotient was 42 at age 6 years. He had axial hypotonia, limb spasticity and dystonia, and severe ataxia. The patient's glucose uptake in red blood cells was 36% of controls. Studies in Xenopus oocytes showed 3.2% residual activity with the R126L-mutant protein and 12.7% residual activity with the K256V-mutant protein.
For discussion of the arg126-to-leu (R126L) mutation in the SLC2A1 gene that was found in compound heterozygous state in a patient with blood-brain barrier glucose transport defect (see 606777) by Wang et al. (2000), see 138140.0004.
Klepper et al. (2001) reported a father and 2 children from separate marriages affected by GLUT1 deficiency (GLUT1DS1; 606777) who were heterozygous for a gly91-to-asp (G91D) substitution in the GLUT1 gene. The father developed generalized tonic-clonic seizures and myoclonic seizures at age 3 years. As an adult, he had mild mental retardation, depression, and migraine. One daughter had mild spastic diplegia at age 9 months and showed developmental delay over the next 2 years. At age 3, she developed complex partial seizures. At age 10 years, she had moderate mental retardation, cerebellar ataxia, and mild pyramidal signs of the legs. The second daughter showed developmental delay, spastic diplegia, and generalized tonic-clonic seizures at age 2. Physical exam at age 22 years revealed moderate mental retardation, cerebellar ataxia, and spastic tetraplegia that predominantly involved the legs. The 2 daughters both had hypoglycorrhachia. The G91D amino acid change was predicted to affect an arg-X-gly-arg-arg motif between helices 2 and 3 that represents a highly conserved cytoplasmic anchor point. The uptake of 3-O-methyl-D-glucose into erythrocytes was significantly reduced, suggesting a quantitatively normal, but functionally impaired, GLUT1 protein at the cell membrane.
Klepper et al. (2001) demonstrated that expression of mutant G91D or G91A in Xenopus oocytes resulted in significantly decreased glucose transport (by about 40%) compared to wildtype. The mutant proteins were present at the plasma membrane at levels comparable to wildtype. Klepper et al. (2001) concluded that the loss of glycine at this position, rather than the introduction of aspartic acid, was responsible for the functional consequences observed in these patients.
In affected members of a family with GLUT1 deficiency (GLUT1DS1; 606777), Brockmann et al. (2001) identified a heterozygous arg126-to-his (R126H) missense mutation in the SLC2A1 gene.
In 4 affected members of a family with paroxysmal exertion-induced dyskinesia and hemolytic anemia (GLUT1DS2; 612126), Weber et al. (2008) identified a heterozygous 12-bp deletion (1022_1033del) in exon 6 of the SLC2A1 gene, resulting in a loss of 4 amino acids within the seventh transmembrane segment, which contains a highly conserved portion of the pore-forming region. The mutation was not detected in 150 controls. Clinical features included childhood onset of episodic involuntary exertion-induced dystonic, choreoathetotic, and ballistic movements. In addition, all affected family members had a history of macrocytic hemolytic anemia with reticulocytosis. Two patients had seizures and 1 had decreased cognitive function with an IQ of 77. In vitro functional expression studies in Xenopus oocytes and human erythrocytes showed that the mutation decreased glucose transport and caused a cation leak that altered intracellular concentrations of sodium, potassium, and calcium. Based on these findings and brain imaging studies, Weber et al. (2008) concluded that the dyskinesias resulted from an exertion-induced energy deficit causing episodic dysfunction in the basal ganglia. The hemolysis resulted from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.
In 5 affected members of a family with GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126), Weber et al. (2008) identified a heterozygous 1119G-A transition in the SLC2A1 gene, resulting in a gly314-to-ser (G314S) substitution in the eighth transmembrane segment. The phenotype was characterized by childhood-onset paroxysmal exertion-induced dyskinesia with epilepsy with absences or complex partial seizures, mild learning disabilities, and an irritable behavior with increased impulsivity in 6 affected members. Hematologic abnormalities were not observed. The mutation was also identified in 2 unaffected family members, indicating decreased penetrance. The mutation was not identified in 150 controls. In vitro functional expression studies showed that the mutation decreased glucose transport but did not affect cation permeability.
In 5 affected members of a family with GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126), Weber et al. (2008) identified a heterozygous 1002G-A transition in the SLC2A1 gene, resulting in an ala275-to-thr (A275T) substitution at the cytoplasmic end of transmembrane segment 7. The mutation was not identified in 150 controls. In vitro functional expression studies showed that the mutation decreased glucose transport but did not affect cation permeability.
In a 6-year-old boy with GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126), Overweg-Plandsoen et al. (2003) identified a de novo heterozygous 280A-T transversion in exon 2 of the GLUT1 gene, resulting in an asn34-to-ile (N34I) substitution in the largest extracellular loop connecting transmembrane domains 1 and 2. He had an atypical phenotype in that he never had seizures. Clinical features included delayed psychomotor development, moderate mental retardation, dysarthria, limb ataxia, hyperreflexia, and dystonic posturing of the arms. The motor activity and coordination fluctuated throughout the day, which was unrelated to food intake. A ketogenic diet helped with the motor symptoms.
In affected members of a large Belgian family segregating paroxysmal exercise-induced dyskinesia with or without epilepsy (GLUT1DS2; 612126), Suls et al. (2008) identified a heterozygous ser95-to-ile (S95I) mutation in exon 4 of the SLC2A1 gene. The mutation resulted from a T-A transversion and a C-T transition at nucleotides 283 and 284, respectively. The mutation occurred in the cytosolic loop connecting transmembrane segments 2 and 3, and was not found in 184 ethnically matched controls. In vitro functional expression studies in Xenopus oocytes showed that the S95I mutant protein caused reduced glucose uptake with a decrease of maximal transport velocity compared to wildtype. Cation permeability was not affected, and none of the patients had hemolytic anemia.
In a 13-year-old boy with GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126), Joshi et al. (2008) identified a heterozygous mutation in the SLC2A1 gene, resulting in an arg93-to-trp (R93W) substitution. The patient had an atypical phenotype, with delayed psychomotor development, early-onset ataxia, and hyperreflexia. He first developed a seizure disorder at age 11 years, with staring spells, head jerking, eye rolling, and loss of tone, which progressed to absence, myoclonic, and atonic seizures. His cognitive and motor skills deteriorated during this period. EEG showed moderate background slowing. Laboratory studies showed decreased CSF glucose and lactate, consistent with GLUT1 deficiency syndrome. A ketogenic diet resulted in complete seizure control with motor and cognitive improvement.
Rotstein et al. (2009) identified a de novo heterozygous R93W mutation in a 10-year-old boy with GLUT1 deficiency. At age 2 years, he had onset of episodic ataxia and slurred speech associated with unilateral muscle weakness. Laboratory studies showed significantly decreased CSF glucose levels. He showed gradual cognitive decline, progressive microcephaly, and ataxia during childhood. Rotstein et al. (2009) noted that the phenotype in this patient was reminiscent of alternating hemiplegia of childhood (104290). Studies of patient erythrocytes showed about a 50% decrease in glucose uptake compared to controls. The R93W substitution occurs in the first cytosolic loop of the protein.
In a 22-year-old Italian woman with GLUT1 deficiency syndrome-1 (GLUT1DS1; 606777), Zorzi et al. (2008) identified a heterozygous de novo mutation in the SLC2A1 gene, resulting in an arg126-to-cys (R126C) substitution. She had delayed psychomotor development, mild mental retardation, microcephaly, dysarthria, and spasticity. She had onset of complex partial seizures at age 4 months. At age 10, she developed paroxysmal exercise-induced leg dystonia. CSF glucose was reduced at 31 mg/dl.
Suls et al. (2009) identified a de novo heterozygous R126C mutation, resulting from a 376C-T transition in exon 4 of the GLUT1 gene, in a 12-year-old girl who developed absence seizures and myoclonus at age 14 months. She had mild gait ataxia, subtle paroxysmal exercise-induced dyskinesia, and moderate mental retardation, consistent with GLUT1DS2 (612126). The mutation occurred in a highly conserved region of transmembrane domain 4, and was not found in 276 control chromosomes. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in decreased glucose transport without affecting glucose binding. Mutations in the same codon (R126L; 138140.0005 and R126H; 138140.0007) have been found in other patients with GLUT1DS1.
Weber et al. (2011) identified a heterozygous R126C mutation in Australian twin brothers with dystonia-9 (DYT9; 601042) and mental retardation. Both had onset in early childhood of paroxysmal choreoathetosis and progressive spastic paraparesis; ataxia was not observed.
In a 25-year-old Caucasian English woman with GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126), Schneider et al. (2009) identified a de novo heterozygous 274C-T transition in the SLC2A1 gene, resulting in an arg91-to-trp (R91W) substitution. The mutation was not found in 382 control chromosomes. The patient developed paroxysmal exercise-induced dyskinesias in early childhood. She also had absence seizures between ages 4 and 10 years, and developed migraine with visual aura at age 11. The migraines were occasionally associated with hemiplegia.
In a 6-year-old girl, born of consanguineous Arab parents from a Bedouin kindred from Qatar, with GLUT1 deficiency syndrome-1 (see 606777), Klepper et al. (2009) identified a homozygous 1402C-T transition in exon 10 of the SLC2A1 gene, resulting in an arg468-to-trp (R468W) substitution. She was noted to have unsteady ataxic gait at age 18 months, as well as paroxysmal choreoathetosis. She also had developmental delay and hypotonia. EEG showed a polymorphic baseline alpha-theta activity with an isolated monomorphic sharp wave focus. Lumbar puncture showed hypoglycorrhachia and decreased CSF lactate. Her clinically asymptomatic 2-year-old sister was also homozygous for the mutation; she was found to have hypoglycorrhachia and decreased CSF lactate. The parents, who were unaffected, were heterozygous for the mutation. Klepper et al. (2009) concluded that the mutation was pathogenic, since the affected residue is highly conserved, is located in the C terminus which is essential for substrate recognition and transport, and was not found in 120 control alleles. Klepper et al. (2009) suggested that the unaffected sister who was homozygous for the mutation was too young for symptom onset. The findings suggested that GLUT1 deficiency can also be inherited in an autosomal recessive pattern.
In a 7-year-old girl with GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126), Perez-Duenas et al. (2009) identified a heterozygous de novo 3-bp insertion (TAT) in the SLC2A1 gene, resulting in addition of a tyrosine at codon 292 in the extracellular boundary of the seventh transmembrane domain, predicted to impair blood-brain glucose flux. She already had delayed psychomotor development but presented at age 5 years with episodic flaccidity and loss of ambulation. The episodes continued and were accompanied by gait ataxia, dysarthria, dyskinesias, and choreic movements. Milder features included action tremor, upper limb dysmetria, and ataxia. Brain MRI showed moderately severe supratentorial cortico-subcortical atrophy, and EEG showed mild diffuse slowing. CSF glucose was decreased. Institution of a ketogenic diet resulted in clinical improvement of the movement disorder and increased brain growth, although cognitive skills did not improve.
In affected members of a large German family with dystonia-9 (DYT9; 601042), originally reported by Auburger et al. (1996), Weber et al. (2011) identified a heterozygous 634C-T transition in the SLC2A1 gene, resulting in an arg212-to-cys (R212C) substitution in the third intracellular loop close to the sixth transmembrane segment. The mutation was not found in 400 control chromosomes. In vitro functional expression studies showed that the mutant protein had normal expression at the cell surface, but decreased glucose uptake compared to wildtype.
In 8 affected members of an Italian family with idiopathic generalized epilepsy-12 (EIG12; 614847), Striano et al. (2012) identified a heterozygous 694C-T transition in the SLC2A1 gene, resulting in an arg232-to-cys (R232C) substitution at a highly conserved residue in the third intracellular loop. The mutation was not found in 846 normal controls. The mutation was also found in 4 healthy adult family members, yielding a penetrance of 67%. In vitro functional studies showed that the mutant protein was expressed at the cell surface, but had mildly decreased glucose uptake (70%) compared to wildtype. The findings suggested that GLUT1 deficiency is a rare cause of typical EIG, and also expanded the phenotypic spectrum associated with mutations in the SLC2A1 gene. The age at seizure onset ranged from early childhood to 23 years. All had generalized seizures, mainly typical absence seizures, and EEG showed regular, symmetric discharges of 3 to 3.5 Hz spike wave complexes. Seizures typically remitted 2 to 5 years after onset, although 1 patient later developed juvenile myoclonic epilepsy. Most showed a favorable response to pharmacologic treatment. None of the patients had other neurologic manifestations, including movement disorders.
In a 28-year old woman with idiopathic generalized epilepsy-12 (EIG12; 614847) manifest as childhood onset of absence seizures at age 3 and generalized seizures at age 7, Suls et al. (2009) identified a heterozygous 668G-C transversion in exon 5 of the SLC2A1 gene, resulting in an arg223-to-pro (R223P) substitution at a residue conserved only in mammals. Intelligence was normal and she was seizure-free with medication since age 7. In vitro functional expression studies showed that the mutant protein had significantly decreased glucose uptake in Xenopus oocytes compared to controls.
Lee et al. (2015) identified serine-226 (S226) in GLUT1 as a protein kinase C (PKC) phosphorylation site. In vitro kinase studies, mass spectrometry, and phosphospecific antibody studies showed that phosphorylation of S226 was required for enhanced cell surface localization of GLUT1 and for a rapid increase in glucose uptake under induced conditions in endothelial cells. Several naturally occurring GLUT1 mutations, including R223P, impaired the phosphorylation of S226, resulting in decreased responsiveness of surface relocalization of GLUT1 despite the presence of endogenous GLUT1.
In a 30-year-old man with idiopathic generalized epilepsy (EIG12; 614847), Arsov et al. (2012) identified a heterozygous c.1372C-T transition in exon 10 of the SLC2A1 gene, resulting in an arg458-to-trp (R458W) substitution at a highly conserved residue. In vitro functional expression studies in Xenopus oocytes showed that the R458W substitution caused a marked reduced in glucose transport. The patient had onset of childhood absence epilepsy at age 6 and developed paroyxsmal exertional dyskinesia in his teens. He also had arm dystonia. The patient's father, who also carried the mutation, had onset of childhood absence seizures at age 7, developed PED as an adult, and had disabling leg dyskinesia when walking. The father's unaffected 66-year-old sister also carried the mutation, indicating incomplete penetrance. The proband was identified from a cohort of 504 probands with IGE who underwent direct sequencing of the SLC2A1 gene. The mutation was not found in 470 controls and had not previously been reported in databases of normal human genetic variation.
In 2 adult brothers with idiopathic generalized epilepsy (EIG12; 614847), Arsov et al. (2012) identified a heterozygous c.1232A-G transition in exon 9 of the SLC2A1 gene, resulting in an asn411-to-ser (N411S) substitution at a highly conserved residue. In vitro functional expression studies in Xenopus oocytes showed that the N411S substitution caused a marked reduced in glucose transport. Both patients developed childhood absence epilepsy at age 6 years; 1 also had juvenile myoclonic epilepsy. The proband was identified from a cohort of 504 probands with IGE who underwent direct sequencing of the SLC2A1 gene. The mutation was not found in 470 controls and had not previously been reported in databases of normal human genetic variation.
In a patient (sdCHC-A) with stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN; 608885), originally reported by Fricke et al. (2004) as patient D-II-2, Flatt et al. (2011) identified a heterozygous G-to-A transition in the SLC2A1 gene, resulting in a gly286-to-asp (G286D) substitution at a highly conserved residue. The G286D mutation was not found in the unaffected parents, in 2 unaffected sibs, or in 35 controls, and Flatt et al. (2011) postulated that it was a de novo mutation. Patient red cells had decreased levels of stomatin (STOM; 133090) at the membrane, but normal levels of SLC2A1 and most other membrane proteins. Confocal imaging studies of developing erythrocytes suggested that the loss of stomatin occurred late during reticulocyte maturation and involved endocytosis. In vitro functional expression assays in Xenopus oocytes showed that the mutant protein did not transport glucose and leaked cations.
In a patient (sdCHC-B) with stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN; 608885), originally reported by Fricke et al. (2004) as patient E-II-1, Flatt et al. (2011) identified a heterozygous in-frame 3-bp deletion (ATCdel), resulting in the deletion of either conserved residues ile435 or ile436 in the C-terminal membrane span TM12. The mutation was not found in 35 controls, but patient relatives were not available for genetic analysis; Flatt et al. (2011) postulated that it was a de novo mutation. In vitro functional expression assays in Xenopus oocytes showed that the mutant protein did not transport glucose and leaked cations.
In a girl with SDCHCN, Bawazir et al. (2012) identified a de novo heterozygous ile435del or ile436del mutation. Red cell cation content showed extremely leaky red cells. Western blot analysis showed that GLUT1 was expressed normally at the red cell membrane, whereas stomatin (STOM1; 133090) levels were decreased. The authors suggested that the multisystem pathology in this disorder likely reflects a combination of glucose transport deficiency at the blood-brain barrier, resulting in neurologic deficits consistent with GLUT1 deficiency syndrome-1 (GLUT1DS1; 606777), and red cell membrane cation defects, resulting in pseudohyperkalemia and red cell hemolysis.
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