Alternative titles; symbols
HGNC Approved Gene Symbol: SLC6A8
SNOMEDCT: 698290008;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:153,687,926-153,696,593 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Cerebral creatine deficiency syndrome 1 | 300352 | X-linked recessive | 3 |
The creatine-phosphocreatine shuttle has important functions in the temporal and spatial maintenance of the energy supply to skeletal and cardiac muscle. Muscle cells do not synthesize creatine, but take it up via a special sodium-dependent transporter, the creatine transporter (SLC6A8). Thus, SLC6A8 has an important role in muscle physiology, and inhibition of creatine transport in experimental animals causes muscle weakness (Gregor et al., 1995).
Using rat Crt1 to probe a human hippocampus cDNA library, Barnwell et al. (1995) obtained 2 groups of CRT clones, which they called CRT1 and CRT2. CRT1 is homologous to rat Crt1. CRT2 encodes a deduced 732-amino acid protein with a unique N-terminal segment and 3 short insertions in its C-terminal half that are not found in CRT1.
Dai et al. (1999) obtained a CRT1 clone from a human heart cDNA library. The deduced protein contains pro285 (P285) rather than ala285 (A285), which was predicted from a CRT1 clone obtained from a human kidney cDNA library by Nash et al. (1994).
Using Western blot analysis, Peral et al. (2002) detected robust expression of an apparent 57-kD CRT protein in human brush border cells. Weaker expression of CRT proteins with apparent molecular masses of 72 and 52 kD was detected in human heart. Immunofluorescence analysis of human ileum detected specific staining at apical membranes of cells lining the villus. In situ hybridization of chicken small intestine showed Crt expression restricted to cells lining the villus, with no Crt expression in crypt cells.
Using RT-PCR analysis, Abplanalp et al. (2013) detected robust SLC6A8 expression in human kidney, retina, brain, heart, and muscle, with weaker expression in lens. In contrast, SLC16A12 (611910), another creatine transporter, was highly expressed in kidney and retina only, with weaker expression in other tissues.
By assaying Xenopus oocytes injected with cRNAs, Dai et al. (1999) found that human CRT1 induced saturable Na(+)- and Cl(-)-dependent creatine uptake. CRT1 forms with P285 were as efficient in creatine uptake as those with A285. However, the P285 form had higher sensitivity to guanidinoethane sulfonic acid, a potent inhibitor of taurine transport, than the A285 form. The substitution did not alter CRT1 sensitivity to other inhibitors tested. Kinetic analysis revealed that 2 Na+ and 1 Cl- were required for electrogenic transport of 1 creatine molecule.
Using Western blot analysis and confocal immunohistochemistry, Schlattner et al. (2002) investigated the localization of creatine kinases (CKs) in mouse and human skin under healthy and pathologic conditions. In mouse skin, they found high amounts of cytosolic brain CK (CKB; 123280) coexpressed with lower amounts of ubiquitous mitochondrial CK (CKMT1B; 123290), both mainly localized in suprabasal layers of the dermis, different cell types of hair follicles, sebaceous glands, and the subcutaneous panniculus carnosus muscle. Except for sebaceous glands, these cells also expressed CRT. Western blot analysis showed that Ckb and Crt were upregulated about 3-fold immediately after wounding of mouse skin, whereas the amount of Ckmt1b increased 10 to 15 days after wounding. Healthy and psoriatic human skin showed a similar coexpression pattern of CKB, CKMT1B, and CRT, with CRT upregulated in psoriasis.
Shojaiefard et al. (2005) showed that human SGK1 (602958) or SGK3 (607591) stimulated creatine-induced currents in Xenopus oocytes heterologously expressing human SLC6A8.
Ji et al. (2019) found that mouse macrophages maintained high intracellular creatine through Slc6a8-mediated uptake and that macrophage polarization was coupled with changes in creatine uptake. Creatine was dispensable for macrophage development and functionality in steady state, but it inhibited polarization of Ifn-gamma (IFNG; 147570)-activated macrophages by suppressing JAK (see 147795)-Stat1 (600555) signaling and Stat1 target gene activation. Consequently, creatine depletion promoted polarization of Ifn-gamma activated macrophages and enhanced host defense against infection by Listeria monocytogenes. Creatine supported polarization of Il4 (147780)-activated macrophages by promoting expression of arginase-1 (ARG1; 608313) through ATP-dependent SWI/SNF (see 600014)-mediated chromatin remodeling.
Sandoval et al. (1996) determined that the SLC6A8 gene contains 13 exons, spans about 8.5 kb of genomic DNA, and is approximately 36 kb centromeric of ALD. Exon 1 occurs within a CpG island, and the gene is transcribed towards the telomeric end.
Gregor et al. (1995) mapped the creatine transporter gene to the X chromosome using somatic cell hybrid panels. They refined the position to Xq28, distal to the G6PD gene, using a second somatic cell hybrid panel containing portions of the X chromosome as the only human DNA. The finding was consistent with the conclusion that the mouse homolog is very close to G6pd (Nash et al., 1994).
Using PCR amplification of genomic DNAs from somatic cell hybrid panels and FISH, Iyer et al. (1996) confirmed the assignment of SLC6A8, which they called CT1, to Xq28. They also identified another creatine transporter locus, SLC6A10, which they called CT2, on chromosome 16p11.2. However, Eichler et al. (1996) and Hoglund et al. (2005) identified SLC6A10 as pseudogene with a premature stop codon in exon 4.
Salomons et al. (2001) described an X-linked cerebral creatine deficiency syndrome (CCDS1; 300352) due to an arg514-to-ter mutation (300036.0001) in the SLC6A8 gene.
Hahn et al. (2002) identified a gly381-to-arg missense mutation in the SLC6A8 gene in a male patient with severe mental retardation with speech and behavioral abnormalities, seizures, short stature, and midface hypoplasia. The underlying mutation, an 1141G-C transversion, had 2 effects: the G381R amino acid substitution and alternative splicing, since the G-to-C transversion occurred at the -1 position of the 5-prime splice junction of intron 7. Two female relatives who were heterozygous for the same SLC6A8 mutation also exhibited mild mental retardation with behavior and learning problems. Male patients with the mutation had highly elevated creatine in their urine and had decreased creatine uptake in fibroblasts, which reflected the deficiency in creatine transport. The ability to measure elevated creatine in urine makes it possible to diagnose SLC6A8 deficiency in male patients with mental retardation of unknown etiology.
The report of Hahn et al. (2002), in conjunction with the reports of arginine:glycine amidinotransferase (AGAT; 602360) deficiency (612718) and of guanidinoacetate methyltransferase (GAMT; 601240) deficiency (612736), clearly indicated the importance of creatine metabolism in brain function.
Rosenberg et al. (2004) studied the prevalence of SLC6A8 mutations in a panel of 290 patients with nonsyndromic X-linked mental retardation archived by the European XLMR Consortium. They found 6 pathogenic mutations, of which 5 were novel, in a total of 288 patients, showing a prevalence of at least 2.1% (6/288). The novel pathogenic mutations were a nonsense mutation (Y317X; 300036.0004), and 4 missense mutations, e.g., G87R (300036.0005) and C337W (300036.0007). They suggested that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1 (309550), the gene responsible for fragile X syndrome (300624). Mandel (2004) stated that this suggestion is 'certainly incorrect.'
Clark et al. (2006) identified 4 pathogenic and 2 potentially pathogenic mutations in the SLC6A8 gene in 6 of 478 unrelated males with X-linked mental retardation, yielding a frequency of approximately 1%. The authors stated that a total of 18 pathogenic mutations in the SLC6A8 gene had been reported, and suggested that urinary screening for an increased creatine:creatinine ratio could lead to focused mutation testing among appropriate patients.
Lion-Francois et al. (2006) identified 4 unrelated patients with severe mental retardation due to X-linked creatine deficiency. Four different mutations were identified in the SLC6A8 gene (see, e.g., 300036.0008; 300036.0009). Together with a fifth case of creatine deficiency due to mutation in the GAMT gene (612736), Lion-Francois et al. (2006) found that the prevalence of cerebral creatine deficiency syndromes was 2.7% in their study population of 188 mentally retarded children. The prevalence rose to 4.4% when only boys were considered.
Valayannopoulos et al. (2012) reported 3 novel mutations in the SLC6A8 gene in 4 male patients with creatine transporter defect.
In a boy with CCDS1, Longo et al. (2024) identified hemizygosity for a missense mutation in the SLC6A8 gene (R278C; 300036.0011). The mutation was identified by sequencing of the SLC6A8 gene. Creatine uptake in patient fibroblasts was 25% of normal activity, and cerebral creatine was 20% of the normal range as measured on MRS.
Levin et al. (2021) found that hemizygous male Scl6a8-null mice had prolonged QTc and left ventricular dilation by 3 months, as well as increased chamber wall thickness, a phenotype not seen in humans. Left ventricular function was normal and unchanged at 9 months. Mouse exercise stress test showed diminished work capacity, and decreased time to exhaustion. Among hemizygous male Scl6a8-null mice, there was remarkable increase in sudden death: 12 of 28 (43%) hemizygous null mice died unexpectedly, while only 1 of 70 (1.4%) wildtype mice died during 40 weeks of observation.
In a male child diagnosed with mild mental retardation at age 6 years who had severe delay in both speech and expressive language function due to cerebral creatine deficiency syndrome-1 (CCDS1; 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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
In a boy with creatine deficiency syndrome (CCDS1; 300352), Longo et al. (2024) identified hemizygosity for a c.832C-T transition in the SLC6A8 gene, resulting in an arg278-to-cys (R278C) substitution. The mutation was identified with sequencing of the SLC6A8 gene. The mutation was reported once (in this patient) in the gnomAD database at an allele frequency of 1/1096567. Creatine uptake in patient fibroblasts was 25% of normal activity and cerebral creatine was 20% of normal as measured on MRS.
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