Glutaric Aciduria Type 1 Metabolites Impair the Succinate Transport from Astrocytic to Neuronal Cells

Lamp, Jessica; Keyser, Britta; Koeller, David M.; Ullrich, Kurt; Braulke, Thomas; Mühlhausen, Chris

doi:10.1074/jbc.m111.232744

Cited by 72 publications

(56 citation statements)

References 37 publications

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“…The Slc13a5 -/-mice do not appear to have seizures (50). It is possible that the Slc13a5 -/-mice are protected from seizures because mice express two citrate transporters, NaCT and NaDC3, on neurons and astrocytes (8), and the citrate might be transported via NaDC3 when NaCT is absent. Rats express NaDC3 on astrocytes and NaCT in neurons (7), and thus may be more likely to develop seizures after inhibition or…”

Section: Resultsmentioning

confidence: 99%

“…The second therapeutic approach would involve using a second citrate transporter in the brain to bypass the inactive NaCT. The related transporter NaDC3 (SLC13A3) carries citrate and it is expressed in brain (7,8), but it is not known whether mutants found in epilepsy patients had activity. The structural models suggest that the mutations alter substrate binding or helix packing, which would be expected to have severe effects on transport function.…”

Section: Discussionmentioning

confidence: 99%

“…The NaCT transporter encoded by SLC13A5 is found on the plasma membrane in liver and brain (5,6). NaCT is found in neurons in rats (7) and both astrocytes and neurons in mice (8). NaCT cotransports sodium and citrate from the extracellular fluid into the cells (5).…”

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confidence: 99%

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Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

Klotz

Porter

Colas

et al. 2016

Mol Med

125

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Mutations in the SLC13A5 gene that codes for the Na + /citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In this study, we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and the treatment strategies. Currently, there are no effective treatments, but some antiepileptic drugs targeting the γ-aminobutyric acid system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical antiseizure medication, decreases seizures in four patients. In contrast to previous reports, the ketogenic diet and fasting resulted in worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improved transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, this study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na + /citrate transporters.online address: http://www.molmed.org

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

Klotz

Porter

Colas

et al. 2016

Mol Med

125

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“…The experimental evidence exists that accumulation of GA and its metabolites may cause complex changes in metabolism due to the inhibitory effect on enzymes and transporters of dicarboxylic acids that may affect energy metabolism including the Krebs cycle (37). These effects in the central nervous system can signifi cantly infl uence the constituents and mechanisms of neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

GAI – distinct genotype and phenotype characteristics in reported Slovak patients

Lisyová¹,

Petrovič²,

Juříčková³

et al. 2017

BLL

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OBJECTIVES: The clinical, biochemical and genetic fi ndings in two Slovak patients with glutaric aciduria type I (GAI) are presented. BACKGROUND: GAI is a rare autosomal recessive neuro-metabolic disorder caused by defi ciency of glutarylCoA dehydrogenase, which is involved in the catabolic pathways of lysine, hydroxylysine and tryptophan. This enzymatic defect gives rise to elevated levels of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC) in body fl uids. METHODS: Biochemical and molecular-genetic tests were performed. Urinary organic acids were analysed by Gas Chromatography/Mass Spectrometry (GC/MS) and the entire coding region of the GCDH gene, including fl anking parts, was sequenced. RESULTS: We found the presence of typical metabolic profi le and novel causal pathogenic variants in both GAI patients. CONCLUSION: We present the fi rst report of two Slovak patients with GAI, which differed in the clinical and biochemical phenotype signifi cantly. They were diagnosed by two distinct approaches -selective and newborn screening. Their diagnosis was complexly confi rmed by biochemical and later on molecular-genetic examinations. Though we agreed with a thesis that early diagnostics might positively infl uenced patientʼs health outcome, contradictory facts should be considered. Supposed extremely low prevalence of GAI patients in the general population and/or the existence of asymptomatic individuals with a questionable benefi t of the applied therapeutic intervention for them lead to doubts whether the inclusion of disease into the newborn screening programme is justifi ed well enough (Tab. 1, Fig. 3

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“…Dikarbonsäure-shuttle) von energiereichen Dikarbonsäuren des Zitratzyklus, z. B. Sukzinat [19]. Dieses Shuttlesystem stellt, ähnlich wie der Glutamat-Glutamin-Zyklus, eine wichtige bioenergetische Kopplung zwischen Astrozyten und Nervenzellen dar.…”

Section: Energiestoffwechselunclassified

Glutarazidurie Typ I

Kölker

Sauer

Okun

et al. 2011

Monatsschr Kinderheilkd

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Von der interdisziplinären Forschung zur strukturierten PatientenversorgungLeitthema Die autosomal-rezessiv vererbte Glutarazidurie Typ I wird durch Mutationen im GCDH-Gen verursacht, die die Funktion des Enzyms Glutaryl-CoADehydrogenase (GCDH) beeinträchti-gen. GCDH ist ein Enzym des Abbauwegs der Aminosäuren L-Lysin, L-Hydroxylysin und L-Tryptophan. Ist seine Funktion gestört, kommt es zur Akkumulation von teilweise neurotoxisch wirkenden Metaboliten, was in schweren zerebralen Schädigun-gen resultiert. Da sich neurologische Symptome durch eine frühzeitige adäquate Versorgung in 95% der Fälle vermeiden lassen, spielen eine früh-zeitige Diagnostik und Therapie eine entscheidende Rolle.

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Glutaric Aciduria Type 1 Metabolites Impair the Succinate Transport from Astrocytic to Neuronal Cells

Cited by 72 publications

References 37 publications

Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

GAI – distinct genotype and phenotype characteristics in reported Slovak patients

Glutarazidurie Typ I

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