scholarly journals SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

2019 ◽  
Author(s):  
Annekatrien Boel ◽  
Joyce Burger ◽  
Marine Vanhomwegen ◽  
Aude Beyens ◽  
Marjolijn Renard ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Glucose Transporter ◽  
Dehydroascorbic Acid ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Human Phenotype ◽  
Knock Out ◽  
Arterial Tortuosity ◽  
Arterial Tortuosity Syndrome ◽  
Knock Out Mice

AbstractArterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicate GLUT10 in transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations do not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in rodents. Gulo;Slc2a10 knock-out mice show mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 knock-out mice do not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. TGFβ signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.

scholarly journals Slc2a10 knock-out mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

2020 ◽  
Vol 29 (9) ◽  
pp. 1476-1488
Author(s):  
Annekatrien Boel ◽  
Joyce Burger ◽  
Marine Vanhomwegen ◽  
Aude Beyens ◽  
Marjolijn Renard ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Transforming Growth Factor Beta ◽  
Glucose Transporter ◽  
Transforming Growth Factor ◽  
Missense Mutations ◽  
Human Phenotype ◽  
Knock Out ◽  
Arterial Tortuosity ◽  
Arterial Tortuosity Syndrome ◽  
Knock Out Mice

Abstract Arterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicated GLUT10 in the transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations did not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in mouse. Gulo;Slc2a10 double knock-out mice showed mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 double knock-out mice did not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. Transforming growth factor beta signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 double knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.

scholarly journals Glucose transporter type 10-lacking in arterial tortuosity syndrome-facilitates dehydroascorbic acid transport

FEBS Letters ◽  
2016 ◽  
Vol 590 (11) ◽  
pp. 1630-1640 ◽  
Author(s):  
Csilla E. Németh ◽  
Paola Marcolongo ◽  
Alessandra Gamberucci ◽  
Rosella Fulceri ◽  
Angiolo Benedetti ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Dehydroascorbic Acid ◽  
Acid Transport ◽  
Arterial Tortuosity ◽  
Arterial Tortuosity Syndrome

Induction of GLUT1 during Erythropoiesis Triggers a Switch from Glucose to DHA Uptake in Vitamin C-Defective Mammals.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1705-1705
Author(s):  
Amelie Montel-Hagen ◽  
Sandrina Kinet ◽  
Nicolas Manel ◽  
Cedric Mongellaz ◽  
Rainer Prohaska ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Glucose Transporter ◽  
Genetic Disorder ◽  
Mammalian Species ◽  
Dehydroascorbic Acid ◽  
Acid Synthesis ◽  
Cell Membrane Permeability ◽  
Compensatory Mechanism ◽  
Red Cell Membrane ◽  
Glut1 Expression

Abstract Glucose provides a key supply of energy and carbon and its transport is achieved via multimembrane-spanning glucose transporters (GLUTs). The human erythrocyte is the cell type expressing the highest level of the GLUT1 glucose transporter, harboring greater than 200,000 molecules per cell. We now demonstrate that GLUT1 transcripts increase by 3-logs during erythropoiesis and high GLUT1 surface expression is observed following passage through the basophilic erythroblast stage. Paradoxically though, glucose transport significantly decreases. As GLUT1 also transports L-dehydroascorbic acid (DHA), the oxidized form of ascorbic acid (AA), transport of this molecule was assessed and indeed, it increases dramatically during erythropoiesis. The switch from glucose to DHA transport is coupled to the physical association of GLUT1 with stomatin, an integral erythrocyte membrane protein. We find that stomatin inversely regulates the relative transports of glucose and DHA by GLUT1. Moreover, in a patient with overhydrated hereditary stomatocytosis, a rare genetic disorder of red cell membrane permeability wherein stomatin is absent, glucose uptake is significantly higher but there is a concomitant 50% reduction in DHA transport. Intriguingly, erythrocyte-specific DHA transport is not conserved amongst all mammalian species; we did not detect GLUT1 on mature murine erythrocytes where DHA uptake is minimal. Notably though, humans differ from the vast majority of the greater than 5,000 mammalian species in that they are unable to synthesize ascorbic acid from glucose. This trait is shared only with other higher primates, guinea pigs and and fruit bats. We have determined that erythrocyte GLUT1 expression and associated DHA transport are specific features of these diverse ascorbic acid-deficient mammals. Within the primate order, defective ascorbic acid synthesis is due to an inactivation of the L-gulonolactone oxidase (GLO) enzyme at the Haplorrhini-Strespsirrhini split. In accord with the data presented above, we find that erythrocyte GLUT1 expression and associated DHA transport are characteristic of erythrocytes from primates within the Haplorrhini suborder but not Strepsirrhini lemurs. Thus, the erythrocyte-specific co-expression of GLUT1 and stomatin constitutes a compensatory mechanism in mammals that are unable to synthesize the essential ascorbic acid metabolite.

scholarly journals Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome

2006 ◽  
Vol 38 (4) ◽  
pp. 452-457 ◽  
Author(s):  
Paul J Coucke ◽  
Andy Willaert ◽  
Marja W Wessels ◽  
Bert Callewaert ◽  
Nicoletta Zoppi ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Arterial Tortuosity ◽  
Arterial Tortuosity Syndrome ◽  
Facilitative Glucose Transporter

scholarly journals NaV1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Isabelle Léna ◽  
Massimo Mantegazza
Keyword(s):  
Wide Spectrum ◽  
Autism Spectrum ◽  
Face Validity ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Knock Out ◽  
Adult Mice ◽  
Ohtahara Syndrome ◽  
Knock Out Mice ◽  
Adolescent Period

Abstract Mutations of the SCN2A gene, encoding the voltage gated sodium channel NaV1.2, have been associated to a wide spectrum of epileptic disorders ranging from benign familial neonatal-infantile seizures to early onset epileptic encephalopathies such as Ohtahara syndrome. These phenotypes may be caused by either gain-of-function or loss-of-function mutations. More recently, loss-of-function SCN2A mutations have also been identified in patients with autism spectrum disorder (ASD) without overt epileptic phenotypes. Heterozygous Scn2a knock-out mice (Scn2a+/−) may be a model of this phenotype. Because ASD develops in childhood, we performed a detailed behavioral characterization of Scn2a+/− mice comparing the juvenile/adolescent period of development and adulthood. We used tasks relevant to ASD and the different comorbidities frequently found in this disorder, such as anxiety or intellectual disability. Our data demonstrate that young Scn2a+/− mice display autistic-like phenotype associated to impaired memory and reduced reactivity to stressful stimuli. Interestingly, these dysfunctions are attenuated with age since adult mice show only communicative deficits. Considering the clinical data available on patients with loss-of-function SCN2A mutations, our results indicate that Scn2a+/− mice constitute an ASD model with construct and face validity during the juvenile/adolescent period of development. However, more information about the clinical features of adult carriers of SCN2A mutations is needed to evaluate comparatively the phenotype of adult Scn2a+/− mice.

scholarly journals Decreased Nuclear Ascorbate Accumulation Accompanied with Altered Genomic Methylation Pattern in Fibroblasts from Arterial Tortuosity Syndrome Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Csilla E. Németh ◽  
Zsófia Nemoda ◽  
Péter Lőw ◽  
Pál Szabó ◽  
Erzsébet Z. Horváth ◽  
...  
Keyword(s):  
Vitamin C ◽  
Epigenetic Regulation ◽  
Dehydroascorbic Acid ◽  
Dna Demethylation ◽  
Nuclear Accumulation ◽  
Specific Gene ◽  
Cultured Fibroblasts ◽  
Arterial Tortuosity ◽  
Arterial Tortuosity Syndrome

Ascorbate requiring Fe2+/2-oxoglutarate-dependent dioxygenases located in the nucleoplasm have been shown to participate in epigenetic regulation of gene expression via histone and DNA demethylation. Transport of dehydroascorbic acid is impaired in the endomembranes of fibroblasts from arterial tortuosity syndrome (ATS) patients, due to the mutation in the gene coding for glucose transporter GLUT10. We hypothesized that altered nuclear ascorbate concentration might be present in ATS fibroblasts, affecting dioxygenase activity and DNA demethylation. Therefore, our aim was to characterize the subcellular distribution of vitamin C, the global and site-specific changes in 5-methylcytosine and 5-hydroxymethylcytosine levels, and the effect of ascorbate supplementation in control and ATS fibroblast cultures. Diminished nuclear accumulation of ascorbate was found in ATS fibroblasts upon ascorbate or dehydroascorbic acid addition. Analyzing DNA samples of cultured fibroblasts from controls and ATS patients, a lower global 5-hydroxymethylcytosine level was found in ATS fibroblasts, which could not be significantly modified by ascorbate addition. Investigation of the (hydroxy)methylation status of specific regions in six candidate genes related to ascorbate metabolism and function showed that ascorbate addition could stimulate hydroxymethylation and active DNA demethylation at the PPAR-γ gene region in control fibroblasts only. The altered DNA hydroxymethylation patterns in patient cells both at the global level and at specific gene regions accompanied with decreased nuclear accumulation of ascorbate suggests the epigenetic role of vitamin C in the pathomechanism of ATS. The present findings represent the first example for the role of vitamin C transport in epigenetic regulation suggesting that ATS is a compartmentalization disease.

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