Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the creatine transporter gene, SLC6A8 (MIM 30036), located in Xq28, have been found in families with X-linked mental retardation (XLMR) as well as in males with idiopathic mental retardation (MR). In order to estimate the frequency of such mutations in the MR population, a screening of 478 males with MR of unknown cause was undertaken. All 13 exons of SLC6A8 were sequenced using genomic DNA. Six novel potentially pathogenic mutations were identified that were not encountered in at least 588 male control chromosomes: two deletions (p.Asn336del, p.Ile347del) and a splice site alteration (c.1016+2C>T) are considered pathogenic based on the nature of the variant. A mutation (p.Arg391Trp) should be considered pathogenic owing to its localization in a highly conserved region. Two other missense variants (p.Lys4Arg, p.Gly26Arg) are not conserved but were not observed in over 300 male control chromosomes. Their pathogenicity is uncertain. A missense variant (p.Val182Met), was classified as a polymorphism based on a normal creatine/creatinine (Cr:Crn) ratio and cerebral creatine signal in proton magnetic resonance spectroscopy (H-MRS) in the patient. Furthermore, we found 14 novel intronic and neutral variants that were not encountered in at least 280 male control chromosomes and should be considered as unclassified variants. Our findings of a minimum of four pathogenic mutations and two potentially pathogenic mutations indicate that about 1% of males with MR of unknown etiology might have a SLC6A8 mutation. Thus, DNA sequence analysis and/or a Cr:Crn urine screen is warranted in any male with MR of unknown cause.
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PMID:X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. 1673 45

Creatine transporter deficiency is an X-linked mental retardation disorder caused by mutations in the creatine transporter gene (SLC6A8). So far, 20 mutations in the SLC6A8 gene have been described. We have developed a diagnostic assay to test creatine uptake in fibroblasts. Additionally, we expanded the assay to characterize novel SLC6A8 missense variants. A total of 13 variants were introduced in the SLC6A8 cDNA by site-directed mutagenesis. All variants were transiently transfected in SLC6A8-deficient fibroblasts and tested for restoration of creatine uptake in deficient primary fibroblasts. Thus, we proved that nine variants (p.Gly87Arg, p.Phe107del, p.Tyr317X, p.Asn336del, p.Cys337Trp, p.Ile347del, p.Pro390Leu, p.Arg391Trp, and p.Pro554Leu) are pathogenic mutations and four variants (p.Lys4Arg, p.Gly26Arg, p.Met560Val, and p.Val629Ile) are nonpathogenic. The present study provides an improved diagnostic tool to classify sequence variants of unknown significance.
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PMID:Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application. 1746 20

Disorders of creatine synthesis or its transporter resulting in neurological impairment with mental retardation and epilepsy have only been recognized in recent years. To date, the epileptic disorder observed in creatine transporter deficiency (CRTR-D) has been described as a mild phenotype with infrequent seizures and favorable response to common antiepileptic drugs. We report on a 5 year-old boy with known speech delay who presented with severe and refractory epilepsy. After extensive investigations, metabolite analysis and brain 1H-MRS suggested CRTR-D, which was confirmed by the detection of a known pathogenic mutation in the SLC6A8 gene (c.1631C>T; p.Pro544Leu).
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PMID:Severe epilepsy in X-linked creatine transporter defect (CRTR-D). 1755 21

We report on a 9.5-year-old Italian boy affected by creatine transporter deficit (CT1), due to a de novo mutation in SLC6A8 gene. The patient was investigated by means of a comprehensive neuropsychological protocol and presented with an unusual alteration of speech and expressive-language function, associated with mental retardation, that differed from CT1 patients described to date. In particular, he exhibited a developmental apraxia of speech (DAS) with motor planning and execution deficit, while receptive language was consistent with his mental age.
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PMID:Mental retardation and verbal dyspraxia in a new patient with de novo creatine transporter (SLC6A8) mutation. 1760 97

Creatine transporter deficiency is an X-linked mental retardation disorder caused by mutations in the creatine transporter gene, SLC6A8. In a European Mental Retardation Consortium panel of 66 patients, we identified a male with mental retardation, caused by a c.1059_1061delCTT; p.Phe354del mutation in the SLC6A8 gene. With the use of direct DNA sequencing, the mutation was also found in the brother of the proband, but not in their mother. However, by analyzing EDTA blood of the mother with denaturing high-performance liquid chromatography (DHPLC), we could show that the mother displays low-level somatic mosaicism for the three base-pair deletion. This study indicates DHPLC as an important tool in the detection of low-level mosaicism, as does it illustrate the importance of considering somatic and germline mosaicism in the case of apparent de novo mutation.
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PMID:Detection of low-level somatic and germline mosaicism by denaturing high-performance liquid chromatography in a EURO-MRX family with SLC6A8 deficiency. 1835 Mar 23

Inherited defects in creatine biosynthesis and cellular uptake are neurometabolic disorders characterized by seizures, developmental delay, mental retardation, autistic-like behavior, and creatine deficiency in the brain. Metabolic screening of these disorders is possible using analytical techniques that quantify creatine and its precursor guanidinoacetate in urine, plasma, or cerebrospinal fluid (CSF). Elevated creatine in urine is suggestive of a deficiency of the X-linked creatine transporter, SLC6A8. Decreased or elevated levels of guanidinoacetate in urine, plasma, or CSF suggest deficiencies of the creatine biosynthetic enzymes, arginine:glycine amidinotransferase (AGAT) or guanidinoacetate methyltransferase (GAMT), respectively. This unit describes three stable isotope dilution-mass spectrometric methods for analyzing creatine and guanidinoacetate. Gas chromatography/mass spectrometry with negative-ion chemical ionization is a highly sensitive technique, suitable for detection of low analyte levels resulting from AGAT deficiency and in CSF. The two liquid chromatography-tandem mass spectrometric approaches are amenable to high-throughput screening and have simple sample preparation requirements.
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PMID:Quantification of creatine and guanidinoacetate using GC-MS and LC-MS/MS for the detection of cerebral creatine deficiency syndromes. 1842 9

Autism is a complex neurodevelopmental disorder characterized by impairment of social interaction, language, communication, and stereotyped, repetitive behavior. Genetic predisposition to autism has been demonstrated in families and twin studies. About 5-10% of autism cases are associated with chromosomal abnormalities or monogenic disorders. The identification of genes involved in the origin of autism is expected to increase our understanding of the pathogenesis. We report on the clinical, cytogenetic, and molecular findings in a boy with autism carrying a de novo translocation t(7;16)(p22.1;p11.2). The chromosome 16 breakpoint disrupts the paralogous SLC6A8 gene also called SLC6A10 or CT2. Predicted translation of exons and RT-PCR analysis reveal specific expression of the creatine transporter paralogous in testis and brain. Several studies reported on the role of X-linked creatine transporter mutations in individuals with mental retardation, with or without autism. The existence of disruption in SLC6A8 paralogous gene associated with idiopathic autism suggests that this gene may be involved in the autistic phenotype in our patient.
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PMID:The creatine transporter gene paralogous at 16p11.2 is expressed in human brain. 1850 88

SLC6A8 deficiency is caused by mutations in the X-linked creatine transporter gene (SLC6A8), which leads to cerebral creatine deficiency, mental retardation, speech and language delay, autistic-like behaviour and epilepsy. Insight in the mechanism of how the transporter is regulated is largely unknown and it is of importance for the development of successful treatment strategies of cerebral creatine deficient syndromes. Our goal was to characterize CRT2 (SLC6A8B), a published splice variant of the creatine transporter. Surprisingly, using RT-PCR we found a novel splice variant, SLC6A8C, which is predominantly found in human tissues with a high energy requirement such as brain, kidney, heart, small intestines and skeletal muscle, where SLC6A8 transporter is most required. The 5' untranslated region (UTR) of the SLC6A8C mRNA was identified using the Smart Race cDNA amplification kit. The SLC6A8C mRNA contains intron 4 and exons 5 through 13 of SLC6A8, including part of the 3' UTR. An open reading frame was found, which predicts a truncated protein identical to the SLC6A8 transporter, comprising the five last C-terminal transmembrane domains of the SLC6A8 transporter. SLC6A8C open reading frame was cloned as a fusion protein with EGFP and the SLC6A8C protein expression was detected by Western Blot. RT-PCR and sequence analysis showed that this splice variant is conserved in evolution, since we also detected it in mouse. This study reveals the presence of a novel SLC6A8 splice variant, SLC6A8C in human and mouse.
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PMID:Identification, characterization and cloning of SLC6A8C, a novel splice variant of the creatine transporter gene. 1851 20

Creatine and phosphocreatine provide an intracellular, high-energy phosphate buffering system, essential to maintain ATP levels in tissues with high energy demands. A specific plasma membrane creatine transporter (CRT) is required for the cellular uptake of creatine. This transporter is related to the gamma-aminobutyric acid (GAT) and norepinephrine (NET) transporters and is part of a large gene family of Na(+) - and Cl(-) -dependent neurotransmitter transporters, now known as solute carrier family 6 (SLC6). CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour. Insight into the structure and function of the CRT has come from studies of creatine transport by tissues and cells, in vitro studies of CRT mutations, identification of mutations associated with CRT deficiency, and from the recent high resolution structure of a prokaryotic homologue of the SLC6 transporters. CRT antibodies have been developed enabling the localization of creatine uptake sites in the brain, retina, muscle and other tissues. These tools in conjunction with the use of appropriate cell models should allow further progress in our knowledge on the regulation and cellular trafficking of the CRT. Development of suitable mouse models may allow improved understanding of the importance of the CRT for normal brain function and how the transporter is regulated in vivo.
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PMID:Functional insights into the creatine transporter. 1865 74

Cerebral creatine deficiency syndromes (CCDSs) are a group of inborn errors of creatine metabolism comprising two autosomal recessive disorders that affect the biosynthesis of creatine--i.e. arginine:glycine amidinotransferase deficiency (AGAT; MIM 602360) and guanidinoacetate methyltransferase deficiency (GAMT; MIM 601240)--and an X-linked defect that affects the creatine transporter, SLC6A8 deficiency (SLC6A8; MIM 300036). The biochemical hallmarks of these disorders include cerebral creatine deficiency as detected in vivo by 1H magnetic resonance spectroscopy (MRS) of the brain, and specific disturbances in metabolites of creatine metabolism in body fluids. In urine and plasma, abnormal guanidinoacetic acid (GAA) levels are found in AGAT deficiency (reduced GAA) and in GAMT deficiency (increased GAA). In urine of males with SLC6A8 deficiency, an increased creatine/creatinine ratio is detected. The common clinical presentation in CCDS includes mental retardation, expressive speech and language delay, autistic like behaviour and epilepsy. Treatment of the creatine biosynthesis defects has yielded clinical improvement, while for creatine transporter deficiency, successful treatment strategies still need to be discovered. CCDSs may be responsible for a considerable fraction of children and adults affected with mental retardation of unknown etiology. Thus, screening for this group of disorders should be included in the differential diagnosis of this population. In this review, also the importance of CCDSs for the unravelling of the (patho)physiology of cerebral creatine metabolism is discussed.
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PMID:Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. 1865 76


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