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. 2022 Nov 4;23(21):13560.
doi: 10.3390/ijms232113560.

Molecular Genetics of GLUT1DS Italian Pediatric Cohort: 10 Novel Disease-Related Variants and Structural Analysis

Alessia Mauri  1   2 , Alessandra Duse  3 , Giacomo Palm  4 , Roberto Previtali  3 , Stefania Maria Bova  3 , Sara Olivotto  3 , Sara Benedetti  2 , Francesca Coscia  4 , Pierangelo Veggiotti  1   3 , Cristina Cereda  2
Affiliations

Molecular Genetics of GLUT1DS Italian Pediatric Cohort: 10 Novel Disease-Related Variants and Structural Analysis

Alessia Mauri et al. Int J Mol Sci. .

Abstract

GLUT1 deficiency syndrome (GLUT1DS1; OMIM #606777) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly, and movement disorders (e.g., spasticity and dystonia). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly, these variants arise de novo resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described. Twenty-seven Italian pediatric patients, clinically suspect of GLUT1DS from both sporadic and familial cases, have been enrolled. We detected by trios sequencing analysis 25 different variants causing GLUT1DS. Of these, 40% of the identified variants (10 out of 25) had never been reported before, including missense, frameshift, and splice site variants. Their structural mapping on the X-ray structure of GLUT1 strongly suggested the potential pathogenic effects of these novel disease-related mutations, broadening the genotypic spectrum heterogeneity found in the SLC2A1 gene. Moreover, 24% is located in a vulnerable region of the GLUT1 protein that involves transmembrane 4 and 5 helices encoded by exon 4, confirming a mutational hotspot in the SLC2A1 gene. Lastly, we investigated possible correlations between mutation type and clinical and biochemical data observed in our GLUT1DS cohort, revealing that splice site and frameshift variants are related to a more severe phenotype and low CSF parameters.

Keywords: GLUT1 deficiency syndrome; GLUT1 structure analysis; novel SLC2A1 variants.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Distribution of 25 different variants in the SLC2A1 gene identified in 27 patients with GLUT1DS. (b) Representation of the GLUT1 protein domains and mapping of 25 different mutations reported in our GLUT1DS patients (adapted from Galochkina et al., 2019 [23]. More details on licensing are available via the following link http://creativecommons.org/licenses/by/4.0/, accessed on 28 October 2022). Novel variants identified in our cohort are reported in bold.
Figure 2
Figure 2
Pedigree of the familial cases with GLUT1DS. In family 2 and family 6, grey fills denote patients with clinical phenotype but unavailable for the study.
Figure 3
Figure 3
(a) Schematic illustration of normal (above) and aberrant splicing (bottom), which results in exon 2 skipping. The red asterisk indicates the novel heterozygous de novo c.114+1G > A variant in intron 2. (b) Relative expression analysis of GLUT1 alternative isoform by RT-qPCR in the patient 3. GLUT1 expression data are normalized on GAPDH expression levels. (c) Sequence electropherograms showing the GLUT1 transcript with skipping of exon 2, resulting from the identified c.114+1G > A mutation, in patient 3 (above). As expected, the full-length GLUT1 transcript was identified in wild-type GLUT1 (bottom).
Figure 4
Figure 4
Novel disease-related mutations mapped on the structure of GLUT1. (a) X-ray structure of human GLUT1 (PDB ID: 6THA) bound to Nonyl-β-D-Glucoside via its glucose head group. Novel disease-related mutations identified in this study are depicted in orange and superimposed on their corresponding wild-type residues. (b), Mutations Leu67Pro and Gly75Glu on transmembrane helix 2 (TMH2) could disrupt the α-helical architecture and the hydrophobicity of the region, respectively. (c) Gln283Lys could hamper the hydrogen bond network that stabilizes glucose binding. (d) Ala377Pro could destabilize the α-helical architecture of TMH10. (e). Thr455Ala potentially breaks the hydrogen bond network between residues on TMH9, TMH10 and TMH12, possibly reducing the stability and rigidity of the C-terminal domain of GLUT1.
Figure 5
Figure 5
Distribution of the 27 SLC2A1 variants observed in our cohort according to the different phenotype.
Figure 6
Figure 6
Genotype, phenotype, and biochemical correlations. (a) Boxplot shows CSF/blood glucose ratios with three different phenotypes. (b) Boxplot displays CSF/blood glucose ratios with different type of variants.
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