br Investigations br Genetics GLUT is a membrane bound glyco
Genetics GLUT1 is a membrane-bound glycoprotein that provides base-rate glucose transport across blood-tissue barriers. It is constituitively expressed in erythrocytes, 4E1RCat synthesis microvessels and astroglia. The gene exclusively associated with GLUT1 is SLC2A1, located on chromosome 1 (1p34.2). In brain, GLUT1 has been detected in two distinct isoforms encoded by the same gene and differing only in their extent of glycosylation: the 55 Kda isoform is located in the endothelial cells of brain microvessels and erythrocytes; the 45 Kda form is detected in most cells including astrocytes and may be responsible for basal glucose uptake into these tissues. A structural model for GLUT1 contains 12 transmembrane domains, spanning the plasma membrane as α-helices with intracellular located amino-and carboxyl-termini. Helices 6 and 7 are separated by the large intercellular loop. The postulated three-dimensional structure is characterized by a central channel across the protein, connecting the extracellular and intracellular enviroments. Crucial domains for transport and pathogenicity are clustered around the central channel and in the long intracellular loop. Most of SCLA1 mutations detected occurred de novo as a sporadic autosomal dominant condition, resulting in GLUT1 haploinsufficiency.3, 18, 20, 48, 49 Recently, however, an autosomal dominant mode of transmission was identified in several unrelated families.5, 6, 25, 34 Finally, Klepper et al., for the first time, have shown that GLUT1-DS can be also transmitted as an autosomal recessive disease: it emphasizes the importance of further clinical and genetic investigations of family members of GLUT1-DS. All mutations are heterozygous and mostly private; in fact, homozygous GLUT1 mutations presumably are lethal in utero, an observation confirmed in GLUT1 knockout mice. Since the first description of GLUT1-DS and the elucidation of its genetic cause, a wide spectrum of around 100 different mutations in the SLC2A1 gene has been described in approximately 160 patients, including large-scale deletions, missense, nonsense, frame shift and splice-site mutations.1, 21, 22, 24, 32, 34, 36, 37, 52, 53, 54, 55, 56, 57 All mutations either lead to absence or loss of function of one of the SLC2A1 alleles. Several hot spots for recurrent mutations have been identified (Asn34, Gly91, Ser113, Arg126, Arg153, Arg264, Thr295, Arg333, Arg93, Arg212, Gly130, Ala155, Arg330).21, 22 Generally, patients with missense mutations often present with moderate to mild symptoms, but genotype–phenotype correlation in GLUT1-DS is complex and it is not yet clearly defined. However, it has been speculated that large-scale deletions, nonsense, frame shift and splice-site mutations result in 50% loss of the GLUT1 protein and are associated with the moderate, classical phenotype of GLUT1-DS. Heterozygous missense mutations with 50–75% residual function are thought to be associated with mild phenotypes. Missense mutations that result in more than 75% residual transport capacity are speculated to be associated with a minimal phenotype with symptoms related to environmental factors, such as fasting or the use of caffeine. In a recent paper, specific relations between genotype and phenotype has been described in 57 newly diagnosed patients with GLUT1-DS: type of mutation was related to the severity of mental retardation and to the occurrence of movement disorders. In particular, a mild mental retardation was found more often in patients with a missense mutation (type A) than in patients with a nonsense, frame shift, splice site, or translation initiation mutation (type B), or multiple exon deletion (type C); movement disorders, whereas, were more frequently seen in patients with type B or C mutations, than in patients with type A mutations. However, severe mental retardation, was found in a few patients with type A mutations and, in contrast, a mild retardation in some patients with type B or C mutations. Additionally, patients with the same mutation displayed a heterogeneous range of type and severity of phenotype; probably, secondary genes and other proteins may be involved in glucose transport and, then, may explain the phenotypic diversity of this disease. Another possible explanation is a modulating effect of DNA variants regulatory elements of the wild-type GLUT1 allele that may modulate the expression level of the GLUT1 transporter.