Identification of an animal sucrose transporter

Meyer, Heiko; Vitavska, Olga; Wieczorek, Helmut

doi:10.1242/jcs.082024

Cited by 61 publications

(69 citation statements)

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“…Finally, the Drosophila gene slc45-1, a homolog of SLC45A1 (and an ortholog of SLC45A2), also encodes a membrane protein that can transport sugar. 8 Collectively, these observations strongly suggest that SLC45A1 is a H þ and glucose symporter.…”

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confidence: 95%

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

Srour

Shimokawa

Hamdan

et al. 2017

The American Journal of Human Genetics

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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...

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mentioning

confidence: 95%

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

Srour

Shimokawa

Hamdan

et al. 2017

The American Journal of Human Genetics

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“…These results suggest that trehalose, as a disaccharide, was a more effective inhibitor of the SCRT-like transporter than phloretin and phloridzin. Trehalose is also a substrate of SCRT in plants and could be also in the SCRT-like transporter in lobster (Meyer, 2011). These results provide evidence toward a disaccharide transporter with glucose as one or both monomers since the 2 glucose molecules of trehalose can effectively inhibit the sucrose binding site on the SCRT-like transporter.…”

Section: D-glucose Phloridzinmentioning

confidence: 71%

“…The first animal membrane disaccharide transporter gene for a sucrose transporter, SCRT, from the genome of the fruit fly, Drosophila melanogaster, facilitating the absorption of the disaccharide sugar in Saccharomyces cerevisiae as a heterologous expression system, was recently reported (Meyer et al, 2011). The gene was identified in Schizosaccharomyces pombe to test the uptake of disaccharide sugars then expressed in in Saccharomyces cerevisiae (Meyer et al, 2011).…”

Section: Figurementioning

confidence: 99%

“…The gene was identified in Schizosaccharomyces pombe to test the uptake of disaccharide sugars then expressed in in Saccharomyces cerevisiae (Meyer et al, 2011). Immunostaining of the late embryonic fly hindgut indicated the localization of SCRT and suggested the nutritional involvement of the sucrose transporter.…”

Section: Figurementioning

confidence: 99%

“…These studies argued that, under certain conditions, a variety of nutrients might be transported across intestinal epithelia as polymers. With this in mind, a hypothesis was formulated that proposed polysaccharide transport, specifically sucrose transport, might also occur in some animal species (Meyer, 2011).…”

Section: Figurementioning

confidence: 99%

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Functional characterization of a putative disaccharide membrane transporter in crustacean intestine

2014

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Mechanisms of transepithelial absorption of dietary sucrose in the American lobster, Homarus americanus, were investigated to determine if disaccharide sugars can be transported across an animal gut intact. Intestines were mounted in a perfusion chamber to measure mucosal to serosal (MS) 14C‐sucrose transport. MS sucrose transport was a hyperbolic function of luminal sugar concentration, suggesting the presence of carrier‐mediated transport. Sodium‐dependent glucose transport inhibitor, phloridzin, partially decreased MS 14C‐sucrose transport, suggesting hydrolysis of 14C‐sucrose to glucose during transport. Phloretin, an inhibitor of Na+‐independent basolateral glucose transport, partially decreased MS 14C‐sucrose transport, suggesting that some 14C‐sucrose radioactivity may be transported to the blood as 14C‐glucose. Decreased MS 14C‐sucrose transport also occurred in the presence of the disaccharide trehalose. Thin‐layer chromatography (TLC) was used to identify the chemical nature of radioactively‐labeled sugars in the bath following transport and revealed that 14C‐sucrose was transported across the intestine largely as an intact molecule. Results suggest that disaccharide sugars may be transported intact across crustacean intestine and provide support for the occurrence of a disaccharide membrane transporter that has not previously been functionally characterized. Grant Funding Source: This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2010‐65

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Regulation of Sucrose Carrier Activities

Kühn

2012

Phloem

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Identification of an animal sucrose transporter

Cited by 61 publications

References 42 publications

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

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

Functional characterization of a putative disaccharide membrane transporter in crustacean intestine

Regulation of Sucrose Carrier Activities

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