Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Inherit Metab Dis
2013 Jan 01;361:103-12. doi: 10.1007/s10545-012-9495-9.
Show Gene links
Show Anatomy links
Functional and electrophysiological characterization of four non-truncating mutations responsible for creatine transporter (SLC6A8) deficiency syndrome.
Valayannopoulos V
,
Bakouh N
,
Mazzuca M
,
Nonnenmacher L
,
Hubert L
,
Makaci FL
,
Chabli A
,
Salomons GS
,
Mellot-Draznieks C
,
Brulé E
,
de Lonlay P
,
Toulhoat H
,
Munnich A
,
Planelles G
,
de Keyzer Y
.
???displayArticle.abstract???
Intellectual disability coupled with epilepsy are clinical hallmarks of the creatine (Cr) transporter deficiency syndrome resulting from mutations in the SLC6A8 gene. So far characterization of pathogenic mutations of SLC6A8 has been limited to Cr uptake. The aim of our study was to characterize the electrogenic and pharmacological properties of non truncating SLC6A8 mutations identified in patients presenting variable clinical severity. Electrophysiological and pharmacological properties of four mutants (including two novel ones) were studied in X. laevis oocyte expression system. Creatine uptake was assessed with [(14)C]-Cr in X. laevis and patients' fibroblasts. Subcellular localization was determined by immunofluorescence and western blot. All mutants were properly targeted to the plasma membrane in both systems. Mutations led to the complete loss of both electrogenic and transport activities in X. laevis and Cr uptake in patients' fibroblasts. Among the Cr analogs tested, guanidinopropionate induced an electrogenic activity with the normal SLC6A8 transporter similar to creatine whereas a phosphocreatine derivative, PCr-Mg-CPLX, resulted in partial activity. SLC6A8 mutants displayed no electrogenic activity with all Cr analogs tested in X. laevis oocytes. Although the mutations altered various domains of SLC6A8 Cr uptake and electrogenic properties were completely inhibited and could not be dissociated. Besides the metabolic functions of Cr, the loss of SLC6A8 electrogenic activity, demonstrated here for the first time, may also play a role in the altered brain functions of the patients.
Ardon,
Creatine transporter deficiency in two half-brothers.
2010, Pubmed
Ardon,
Creatine transporter deficiency in two half-brothers.
2010,
Pubmed
Arias,
Creatine transporter deficiency: prevalence among patients with mental retardation and pitfalls in metabolite screening.
2007,
Pubmed
Ben-Yona,
A glutamine residue conserved in the neurotransmitter:sodium:symporters is essential for the interaction of chloride with the GABA transporter GAT-1.
2011,
Pubmed
,
Xenbase
Betsalel,
Detection of low-level somatic and germline mosaicism by denaturing high-performance liquid chromatography in a EURO-MRX family with SLC6A8 deficiency.
2008,
Pubmed
Betsalel,
Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database.
2011,
Pubmed
Bizzi,
X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8.
2002,
Pubmed
Brosnan,
New insights into creatine function and synthesis.
2007,
Pubmed
Cecil,
Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect?
2001,
Pubmed
Chen,
Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6.
2004,
Pubmed
Clark,
X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology.
2006,
Pubmed
Cougnon,
Effect of reactive oxygen species on NH4+ permeation in Xenopus laevis oocytes.
2002,
Pubmed
,
Xenbase
Dai,
Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase
Dinour,
A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects.
2004,
Pubmed
,
Xenbase
Dodd,
Selective amino acid substitutions convert the creatine transporter to a gamma-aminobutyric acid transporter.
2007,
Pubmed
Gether,
Neurotransmitter transporters: molecular function of important drug targets.
2006,
Pubmed
Guimbal,
A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression.
1993,
Pubmed
Hahn,
X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28.
2002,
Pubmed
Kathöfer,
Functional coupling of human beta 3-adrenoreceptors to the KvLQT1/MinK potassium channel.
2000,
Pubmed
,
Xenbase
Lion-François,
High frequency of creatine deficiency syndromes in patients with unexplained mental retardation.
2006,
Pubmed
Lunardi,
The creatine transporter mediates the uptake of creatine by brain tissue, but not the uptake of two creatine-derived compounds.
2006,
Pubmed
Nessler,
Evidence for activation of endogenous transporters in Xenopus laevis oocytes expressing the Plasmodium falciparum chloroquine resistance transporter, PfCRT.
2004,
Pubmed
,
Xenbase
Newmeyer,
Incidence of brain creatine transporter deficiency in males with developmental delay referred for brain magnetic resonance imaging.
2005,
Pubmed
Ohana,
Determinants of coupled transport and uncoupled current by the electrogenic SLC26 transporters.
2011,
Pubmed
Puusepp,
The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation.
2010,
Pubmed
Reith,
The importance of company: Na+ and Cl- influence substrate interaction with SLC6 transporters and other proteins.
2006,
Pubmed
Rosenberg,
High prevalence of SLC6A8 deficiency in X-linked mental retardation.
2004,
Pubmed
Rosenberg,
Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application.
2007,
Pubmed
Salomons,
X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.
2001,
Pubmed
Sora,
The cloning and expression of a human creatine transporter.
1994,
Pubmed
Tran,
Cyclosporin A inhibits creatine uptake by altering surface expression of the creatine transporter.
2000,
Pubmed
,
Xenbase
Valayannopoulos,
Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect.
2012,
Pubmed
Wallimann,
Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis.
1992,
Pubmed
Wyss,
Creatine and creatinine metabolism.
2000,
Pubmed
Yamazaki,
Functional characterization of nonsynonymous single nucleotide polymorphisms in the electrogenic Na+-HCO3- cotransporter NBCe1A.
2011,
Pubmed
,
Xenbase
