.. _SLC6A8: SLC6A8 ^^^^^^ .. contents:: :local: General Information ******************* :Full gene name: solute carrier family 6 (neurotransmitter transporter, creatine), member 8 :Entrez Gene ID: 6535 :Location: Xq28 :Synonyms: CRTR, CT1, CRT :Type: protein-coding User SNPs ********* SNPs given by the user that are near or inside this gene: +-----------+---------------+-----------+ | SNP | Distance (bp) | Direction | +===========+===============+===========+ | rs3020789 | 60765 | upstream | +-----------+---------------+-----------+ .. _SLC6A8 Gene summary: NCBI Summary ************ The protein encoded by this gene is a plasma membrane protein whose function is to transport creatine into and out of cells. Defects in this gene can result in X-linked creatine deficiency syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008] .. _OMIM ID 300036 : http://omim.org/entry/300036 .. _SLC6A8 OMIM Text: OMIM **** :OMIM ID: `OMIM ID 300036 `_ **Allelic Variants (Selected Examples)** .0001 CREATINE DEFICIENCY SYNDROME, X-LINKED In a male child diagnosed with mild mental retardation at age 6 years who had severe delay in both speech and expressive language function as well as creatine deficiency (300352), Salomons et al. (2001) found a hemizygous C-to-T transition in exon 11 of the SLC6A8 gene, resulting in an arg514-to-ter (R514X) mutation. Proton magnetic resonance spectroscopy of the child's brain revealed absence of the creatine signal. However, creatine levels in urine and plasma were increased, and guanidinoacetate levels were normal. In 3 female relatives of the index patient, mild biochemical abnormalities and learning disabilities were present to various extents. The 3 female relatives were heterozygous for this mutation. .0002 CREATINE DEFICIENCY SYNDROME, X-LINKED Hahn et al. (2002) described a family in which 5 males in a sibship of 10 had mental retardation with seizures associated with a defect in creatine metabolism (300352). Mutation analysis revealed an 1141G-C transversion at the -1 position of the exon 7/intron 7 splice junction of the SLC6A8 gene. This resulted in the gly381-to-arg missense change and interference with the 5-prime splice junction of intron 7. Subsequent biochemical analyses confirmed a defect in creatine metabolism in this family. The level of urinary creatine was substantially increased in affected male patients and creatine uptake in fibroblasts was decreased. Two sisters of the 5 affected males were heterozygous for the SLC6A8 mutation and exhibited mild mental retardation with behavior and learning problems. .0003 CREATINE DEFICIENCY SYNDROME, X-LINKED Bizzi et al. (2002) reported a child with creatine deficiency (300352) who had severe neurologic disturbances including seizures, behavioral problems, speech delay, and inability to engage in structured play. Proton magnetic resonance spectroscopic imaging showed absence of creatine in the whole brain, which was not corrected by creatine supplementation. Analysis of the SLC6A8 gene showed a hemizygous 3-bp deletion in exon 8, 1221delTTC, resulting in the deletion of a single phenylalanine at residue 408 in a conserved region of the protein. The patient's mother was heterozygous for the mutation. .0004 CREATINE DEFICIENCY SYNDROME, X-LINKED In the index patient of a family with X-linked mental retardation, due to a defect in creatine metabolism (300352), Rosenberg et al. (2004) found an insertion of adenosine at cDNA position 950 in exon 6 of the SLC6A8 gene (950_951insA), resulting in a premature stop (tyr317 to stop, Y317X). The truncated mutant protein was predicted to lack 319 C-terminal residues, including transmembrane domains VII through XII, and to be unstable and/or inappropriately folded and therefore completely inactive. .0005 CREATINE DEFICIENCY SYNDROME, X-LINKED In the index patient of a family with X-linked mental retardation due to a defect in creatine metabolism (300352), Rosenberg et al. (2004) found a G-to-A transition at cDNA position 259 in exon 1 of the SLC6A8 gene that gave rise to a gly87-to-arg (G87R) amino acid substitution. This mutation changes one of 3 glycines that make up a short repeat between transmembrane domains I and II, in a small intracellular loop that is highly conserved among all known creatine transporters and within the neurotransmitter transporter family SLC6. .0006 CREATINE DEFICIENCY SYNDROME, X-LINKED In a male patient with X-linked creatine deficiency syndrome and severe mental retardation (300352), Schiaffino et al. (2005) identified an A-to-G transition in intron 1 of the SLC6A8 gene, resulting in skipping of the first 21 amino acids of exon 2. These residues form the second transmembrane domain, which is highly conserved. .0007 CREATINE DEFICIENCY SYNDROME, X-LINKED In 2 brothers with X-linked creatine deficiency syndrome and mental retardation (300352), Rosenberg et al. (2004) identified a 1011C-G transversion, resulting in a cys337-to-trp (C337W) substitution in the highly conserved intracellular loop between transmembrane domains VI and VII. In the urine of the 2 patients, an increased creatine:creatinine ratio was found, which is a biochemical hallmark of SLC6A8 deficiency. The sister of the patients was a carrier of the C337W mutation. .0008 CREATINE DEFICIENCY SYNDROME, X-LINKED In a 4-year-old boy with creatine deficiency syndrome and severe mental retardation (300352), Lion-Francois et al. (2006) identified a 395G-T transversion in the SLC6A8 gene, resulting in a gly132-to-val (G132V) substitution. The patient had delayed onset of walking and autistic behavior. .0009 CREATINE DEFICIENCY SYNDROME, X-LINKED In a 14-year-old boy with creatine deficiency syndrome and severe mental retardation (300352), Lion-Francois et al. (2006) identified a 1473C-G transversion in the SLC6A8 gene, resulting in a cys491-to-trp (C491W) substitution. The patient had delayed onset of walking, seizures, and autistic features. Brain imaging showed atrophy of the left caudate and hippocampus and a thin corpus callosum. .0010 CREATINE DEFICIENCY SYNDROME, X-LINKED In a 6-year-old boy with creatine deficiency syndrome (300352), Clark et al. (2006) identified a hemizygous 3-bp deletion (1006delAAC) in exon 6 of the SLC6A8 gene, resulting in a deletion of a highly conserved residue asn336. The patient had moderate mental retardation, attention deficit-hyperactivity disorder, microcephaly, and tall stature. Battini et al. (2007) identified the 1006delAAC mutation in a 9.5-year-old Italian boy with mental retardation and verbal dyspraxia. He had delayed psychomotor development, hypotonia, seizures, and severe language deficit with oral-motor dyspraxia, irritability, and temper tantrums. Detailed language evaluation showed problems in picture naming and phonetics, whereas receptive vocabulary was less severely affected. Social interaction was good despite the severe expressive limitation. Battini et al. (2007) noted that the phenotype in their patient was different than that reported by Clark et al. (2006). .. _SLC6A8 Phenotype: NCBI Phenotypes *************** * Gene Reviews * GTR * OMIM * Creatine deficiency, X-linked .. _SLC6A8 GO Term: Gene Ontology ************* * integral to membrane * plasma membrane * creatine transporter activity * neurotransmitter:sodium symporter activity * molecular_function * transport * cellular nitrogen compound metabolic process * muscle contraction * creatine:sodium symporter activity * cellular_component * small molecule metabolic process * choline transmembrane transporter activity * biological_process * integral to plasma membrane * creatine metabolic process * creatine transport .. _SLC6A8 Pathway: KEGG Pathways ************* No pathways found linked to this gene. .. _SLC6A8 GeneRIF: GeneRIFs ******** * involvement of residues from transmembrane domain 3 is a common feature of the substrate pathway of the creatine transporter [`PMID 16049011`_] * Affinity Capture-MS [`PMID 21987572`_] * analysis of X-linked creatine transporter defect in nine boys shows that it has an effect on IQ [`PMID 21556832`_] * Guanidinoacetate is transported from AGAT- to GAMT-expressing cells through SLC6A8 to allow creatine synthesis, thereby explaining creatine deficiency in SLC6A8-deficient CNS. [`PMID 19879361`_] * Hemizygosity for a novel deletion producing a frameshift (c.974_975delCA, p.Thr325SerfsX139) in the creatine transporter gene is associated with X-linked cerebral creatine deficiency. [`PMID 20602486`_] * Missense mutations in SLC6A8 gene is associated with X-linked disorder. [`PMID 22281021`_] * X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28 [`PMID 11898126`_] * SLC6A8 genes may not be directly involved in human male infertility [`PMID 21190923`_] * This study reveals the presence of a novel SLC6A8 splice variant, SLC6A8C in human and mouse. [`PMID 18515020`_] * Heterozygous SLC6A8 deficiency is a potentially treatable condition and should be considered in females with intractable epilepsy and developmental delay/intellectual disabilit [`PMID 20846889`_] * Creatine transporter deficiency associated with gene deficiency of this protein. [`PMID 16086185`_] * Exhibition of a developmental apraxia of speech with motor planning and execution deficit in a creatine transporter (SLC6A8) mutation. [`PMID 17603797`_] * Mutations in the creatine transporter gene SLC6A8 may be a relatively major contributor in males with mental retardation of unknown cause. [`PMID 16738945`_] * symptoms of the creatine transporter defect (mental retardation, learning difficulties, and constipation) can be present in female SLC6A8 heterozygotes [`PMID 20528887`_] * Evidence for a functional involvement of the four mutations affecting ATRX (p.1761M4T), PQBP1 (p.155R4X), and SLC6A8 (p.390P4L and p.477S4L), in the etiology of intellectual disability. [`PMID 21267006`_] * SGK1 and SGK3 increase SLC6A8 activity by increasing the maximal transport rate of the carrier. Deranged SGK1 and/or SGK3 dependent regulation of SLC6A8 may affect energy storage particularly in skeletal muscle, heart, and neurons [`PMID 16036218`_] * High prevalence of SLC6A8 deficiency in X-linked mental retardation [`PMID 15154114`_] * The estimated amount of total creatine in the placenta and brain significantly increased in the second half of pregnancy, coinciding with a significant increase in expression of CrT mRNA. [`PMID 19570237`_] * Observational study of gene-disease association. (HuGE Navigator) [`PMID 18461508`_] * A novel deletion (c.1690-1703 del) in exon 12 of SLC6A8 resulted in a frameship mutation associated with global developmental delay and premature ventricular beats. [`PMID 18443316`_] * impact of creatine deficiency syndrome mutations, CRTR and GAMT on metabolic stress was analyzed in patient fibroblast cultures [`PMID 21140503`_] * X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8. [`PMID 12210795`_] * identified two brothers with mental retardation, caused by a c.1059_1061delCTT; p.Phe354del mutation in the SLC6A8 gene [`PMID 18350323`_] * The frequency of SLC6A8 deficiency was 2.3% in 157 males at risk. [`PMID 19188083`_] .. _PMID 16049011: http://www.ncbi.nlm.nih.gov/pubmed/16049011 .. _PMID 21987572: http://www.ncbi.nlm.nih.gov/pubmed/21987572 .. _PMID 21556832: http://www.ncbi.nlm.nih.gov/pubmed/21556832 .. _PMID 19879361: http://www.ncbi.nlm.nih.gov/pubmed/19879361 .. _PMID 20602486: http://www.ncbi.nlm.nih.gov/pubmed/20602486 .. _PMID 22281021: http://www.ncbi.nlm.nih.gov/pubmed/22281021 .. _PMID 11898126: http://www.ncbi.nlm.nih.gov/pubmed/11898126 .. _PMID 21190923: http://www.ncbi.nlm.nih.gov/pubmed/21190923 .. _PMID 18515020: http://www.ncbi.nlm.nih.gov/pubmed/18515020 .. _PMID 20846889: http://www.ncbi.nlm.nih.gov/pubmed/20846889 .. _PMID 16086185: http://www.ncbi.nlm.nih.gov/pubmed/16086185 .. _PMID 17603797: http://www.ncbi.nlm.nih.gov/pubmed/17603797 .. _PMID 16738945: http://www.ncbi.nlm.nih.gov/pubmed/16738945 .. _PMID 20528887: http://www.ncbi.nlm.nih.gov/pubmed/20528887 .. _PMID 21267006: http://www.ncbi.nlm.nih.gov/pubmed/21267006 .. _PMID 16036218: http://www.ncbi.nlm.nih.gov/pubmed/16036218 .. _PMID 15154114: http://www.ncbi.nlm.nih.gov/pubmed/15154114 .. _PMID 19570237: http://www.ncbi.nlm.nih.gov/pubmed/19570237 .. _PMID 18461508: http://www.ncbi.nlm.nih.gov/pubmed/18461508 .. _PMID 18443316: http://www.ncbi.nlm.nih.gov/pubmed/18443316 .. _PMID 21140503: http://www.ncbi.nlm.nih.gov/pubmed/21140503 .. _PMID 12210795: http://www.ncbi.nlm.nih.gov/pubmed/12210795 .. _PMID 18350323: http://www.ncbi.nlm.nih.gov/pubmed/18350323 .. _PMID 19188083: http://www.ncbi.nlm.nih.gov/pubmed/19188083 .. _SLC6A8 Pubmed: PubMed Articles *************** *Recent articles:* * Betsalel OT et al. "Detection of variants in SLC6A8 and functional analysis of unclassified missense variants." Mol Genet Metab. 2012 Apr;105(4):596-601. `PMID 22281021`_ * van de Kamp JM et al. "Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect." J Inherit Metab Dis. 2012 Jan;35(1):141-9. `PMID 21556832`_ * Lee KA et al. "Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels." J Biol Chem. 2011 Dec 2;286(48):41530-8. `PMID 21987572`_ * Kim W et al. "Systematic and quantitative assessment of the ubiquitin-modified proteome." Mol Cell. 2011 Oct 21;44(2):325-40. `PMID 21906983`_ * Jensen LR et al. "Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1." Eur J Hum Genet. 2011 Jun;19(6):717-20. `PMID 21267006`_ * Alcaide P et al. "Defining the pathogenicity of creatine deficiency syndrome." Hum Mutat. 2011 Mar;32(3):282-91. `PMID 21140503`_ * van de Kamp JM et al. "Clinical features and X-inactivation in females heterozygous for creatine transporter defect." Clin Genet. 2011 Mar;79(3):264-72. `PMID 20528887`_ * Iqbal F et al. "Molecular analysis of guanidinoacetate-n-methyltransferase (GAMT) and creatine transporter (SLC6A8) gene by using denaturing high pressure liquid chromatography (DHPLC) as a possible source of human male infertility." Pak J Pharm Sci. 2011 Jan;24(1):75-9. `PMID 21190923`_ * Mercimek-Mahmutoglu S et al. "Treatment of intractable epilepsy in a female with SLC6A8 deficiency." Mol Genet Metab. 2010 Dec;101(4):409-12. `PMID 20846889`_ * Ardon O et al. "Creatine transporter deficiency in two half-brothers." Am J Med Genet A. 2010 Aug;152A(8):1979-83. `PMID 20602486`_ .. _PMID 20602486: http://www.ncbi.nlm.nih.gov/pubmed/20602486 .. _PMID 21140503: http://www.ncbi.nlm.nih.gov/pubmed/21140503 .. _PMID 20528887: http://www.ncbi.nlm.nih.gov/pubmed/20528887 .. _PMID 21190923: http://www.ncbi.nlm.nih.gov/pubmed/21190923 .. _PMID 21987572: http://www.ncbi.nlm.nih.gov/pubmed/21987572 .. _PMID 21267006: http://www.ncbi.nlm.nih.gov/pubmed/21267006 .. _PMID 20846889: http://www.ncbi.nlm.nih.gov/pubmed/20846889 .. _PMID 21556832: http://www.ncbi.nlm.nih.gov/pubmed/21556832 .. _PMID 21906983: http://www.ncbi.nlm.nih.gov/pubmed/21906983 .. _PMID 22281021: http://www.ncbi.nlm.nih.gov/pubmed/22281021 *Top Pubmed articles linked to gene SLC6A8 matching any search term:* * Shojaiefard M et al. "Downregulation of the creatine transporter SLC6A8 by JAK2." J Membr Biol. 2012 Mar;245(3):157-63. `PMID 22407360`_ * Alesutan IS et al. "Regulation of the glutamate transporter EAAT4 by PIKfyve." Cell Physiol Biochem. 2010;25(2-3):187-94. `PMID 20110679`_ * Tachikawa M et al. "A novel relationship between creatine transport at the blood-brain and blood-retinal barriers, creatine biosynthesis, and its use for brain and retinal energy homeostasis." Subcell Biochem. 2007;46:83-98. `PMID 18652073`_ * Strutz-Seebohm N et al. "PIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8." Cell Physiol Biochem. 2007;20(6):729-34. `PMID 17982255`_ * Boddaert N et al. "[Radiological innovations in the screening and diagnosis of the inborn errors of metabolism]." Med Sci (Paris). 2005 Nov;21(11):981-6. `PMID 16274650`_ .. _PMID 22407360: http://www.ncbi.nlm.nih.gov/pubmed/22407360 .. _PMID 18652073: http://www.ncbi.nlm.nih.gov/pubmed/18652073 .. _PMID 17982255: http://www.ncbi.nlm.nih.gov/pubmed/17982255 .. _PMID 20110679: http://www.ncbi.nlm.nih.gov/pubmed/20110679 .. _PMID 16274650: http://www.ncbi.nlm.nih.gov/pubmed/16274650