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)

ICF syndrome is a rare autosomal recessive disorder characterized by immunodeficiency, centromeric instability, and facial anomalies. It is caused by mutations in a de novo DNA methyltransferase gene, DNMT3B. We here report the first three Japanese cases of ICF syndrome from two unrelated families. All patients had typical facial dysmorphism and immunoglobulin A (IgA) deficiency, but none of them had apparent mental retardation. Cytogenetic analysis of peripheral blood lymphocytes showed chromosomal abnormalities, including multiradial configurations and a stretching of the pericentromeric heterochromatin of chromosomes 1 and 16. Hypomethylation of classical satellite 2 DNA was also observed. Mutation analyses of DNMT3B revealed three novel mutations: patient 1 from the first family was a compound heterozygote for a nonsense mutation (Q42Term) and a missense mutation (R832Q); patients 2 and 3 from the second family were both homozygous for a missense mutation (S282P). The R832Q mutation occurred within the conserved methyltransferase domain, and thus may affect the enzyme activity directly. The S282P mutation, on the other hand, occurred close to the PWWP domain, which is presumably involved in protein-protein interaction. This is the first missense mutation mapped to the N-terminal half of the protein, suggesting that the region plays an important role in the regulation of the DNMT3B enzyme.
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PMID:Three novel DNMT3B mutations in Japanese patients with ICF syndrome. 1223 17

Arginine:glycine amidinotransferase (AGAT, EC 2.1.4.1) deficiency is a recently recognized autosomal recessive inborn error of creatine biosynthesis, characterized by mental retardation and severe language impairment. We extensively investigated a third 5-year-old patient with AGAT deficiency, discovered in the pedigree of the same Italian family as the two index cases. At the age of 2 years he presented with psychomotor and language delay, and autistic-like behavior. Brain MRI was normal, but brain 1H-MRS disclosed brain creatine depletion, which almost completely normalized following creatine monohydrate supplementation. A remarkable clinical improvement paralleled the restoration of brain creatine concentration. AGAT and GAMT (guanidinoacetate:methyltransferase) genes were analyzed in the proband and in 26 relatives, including the two cousins with AGAT deficiency. Sequencing of the proband's AGAT gene disclosed the same homozygous mutation at nt position 9093 converting a tryptophan (TGG) to a stop codon (TAG) at residue 149 (W149X), as already described in the two previously reported cases. The proband's parents and 10 additional subjects of the pedigree were carriers for this mutation. AGAT deficiency was further confirmed by undetectable AGAT activity in the patient's lymphoblasts. Mutation analysis of the GAMT gene revealed a sequence variation in exon 6 (T209M), not in the proband, but in 15 additional subjects from the pedigree. The silent nature of this sequence variation is supported by its homozygosity in one AGAT deficient cousin and in one asymptomatic adult, both with normal GAMT activity.
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PMID:Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. 1246 79

Creatine deficiency syndromes are a newly described group of inborn errors of creatine synthesis (arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoaceteate methyltransferase (GAMT) deficiency) and creatine transport (creatine transporter (CRTR) deficiency). The common clinical denominator of creatine deficiency syndromes is mental retardation and epilepsy, suggesting the main involvement of cerebral grey matter (grey matter disease). Patients with GAMT deficiency exhibit a more complex clinical phenotype with dystonic hyperkinetic movement disorder and epilepsy that in some cases is unresponsive to pharmacological treatment. The common biochemical denominator of creatine deficiency syndromes is cerebral creatine deficiency which is demonstrated by in vivo proton magnetic resonance spectroscopy. Measurement of guanidinoacetate in body fluids may discriminate GAMT (high concentration), AGAT (low concentration) and CRTR (normal concentration). Further biochemical characteristics include changes in creatine and creatinine concentrations in body fluids. GAMT and AGAT deficiency are treatable by oral creatine supplementation, while patients with CRTR deficiency do not respond to this type of treatment. Further recognition of patients will be of major importance for the estimation of the frequency, for the understanding of phenotypic variations and for treatment strategies.
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PMID:Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. 1288 68

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive error of creatine synthesis characterized by cerebral creatine deficiency, accumulation of guanidinoacetate, mental retardation, epilepsy and extrapyramidal signs. So far, six mutations have been identified in seven patients. We investigated seven new patients by screening the promoter, 3'UTR, and six exons and exon/intron boundaries using direct sequencing and denaturing gradient gel electrophoresis. The clinical and biochemical phenotype was characterized by scoring the degree of main clinical manifestations and by determination of urinary guanidinoacetate concentrations and of GAMT activity in fibroblasts / lymphoblasts, respectively. We identified 7 novel mutations, including c.64dupG (exon 1; 4/14 alleles); c.59G>C (exon 1; 3/14 alleles); c.491delG (exon 5; 2/14 alleles); c.160G>C (exon 1; 2/14 alleles); and c.152A>C (exon 1; 1/14 alleles); c.526dupG (exon 5; 1/14 alleles); c.521G>A (exon 5; 1/14 alleles), and two polymorphisms c.626C>T (exon 6) and c.459+71G>A (intron 4). Frameshift and missense mutations in exon 1 were prevalent in the 4 patients with the severe phenotype, however a clear genotype-phenotype correlation has not been established in the limited number of patients characterized so far.
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PMID:Characterization of seven novel mutations in seven patients with GAMT deficiency. 1510 90

Nonsyndromic X-linked mental retardation (NSXLMR) is a very heterogeneous condition, and most of the underlying gene defects are still unknown. Recently, we have shown that approximately 30% of these genes cluster on the proximal Xp, which prompted us to perform systematic mutation screening in brain-expressed genes from this region. Here, we report on a novel NSXLMR gene, FTSJ1, which harbors mutations in three unrelated families--one with a splicing defect, one with a nonsense mutation, and one with a deletion of one nucleotide. In two families, subsequent expression studies showed complete absence or significant reduction of mutant FTSJ1 transcripts. FTSJ1 protein is a homolog of Escherichia coli RNA methyltransferase FtsJ/RrmJ and may play a role in the regulation of translation. Further studies aim to elucidate the function of human FTSJ1 and its role during brain development.
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PMID:Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation. 1516 22

Mental retardation is the most frequent cause of serious handicap in children and young adults. The underlying causes of this heterogeneous condition are both acquired and genetically based. A recently performed refinement of the linkage interval in a large Belgian family with mild to severe non-syndromic X linked mental retardation, classified as MRX9, revealed a candidate region of 11.3 Mb between markers DXS228 and DXS1204 on the short arm of the X chromosome. In order to identify the underlying disease gene in the MRX9 family, we established a gene catalogue for the candidate region and performed comprehensive mutation analysis by direct sequencing. A human homologue of the bacterial 23S rRNA methyltransferase Fstj, the FTSJ1 gene, is located within this region and displayed a sequence alteration in the conserved acceptor splice site of intron 3 (IVS3-2A>G) in all tested patients and carrier females of this family. In contrast, it was absent in all unaffected male family members tested. The mutation results in skipping of exon 4 and introduces a premature stop codon in exon 5, probably leading to a severely truncated protein. Our finding indicates that a protein, possibly associated with ribosomal stability, can be linked to X linked mental retardation (XLMR).
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PMID:A splice site mutation in the methyltransferase gene FTSJ1 in Xp11.23 is associated with non-syndromic mental retardation in a large Belgian family (MRX9). 1534 98

The Immunodeficiency, Centromeric instability, and Facial (ICF) syndrome is a rare autosomal recessive disorder that results from mutations in the DNMT3B gene, encoding a DNA-methyltransferase that acts on GC-rich satellite DNAs. This syndrome is characterized by immunodeficiency, facial dysmorphy, mental retardation of variable severity and chromosomal abnormalities that essentially involve juxtacentromeric heterochromatin of chromosomes 1 and 16. These abnormalities demonstrate that hypomethylation of satellite DNA can induce alterations in the structure of heterochromatin. In order to investigate the effect of DNA hypomethylation on heterochromatin organization, we analyzed the in vivo distribution of HP1 proteins, essential components of heterochromatin, in three ICF patients. We observed that, in a large proportion of ICF G2 nuclei, all HP1 isoforms show an aberrant signal concentrated into a prominent bright focus that co-localizes with the undercondensed 1qh or 16qh heterochromatin. We found that SP100, SUMO-1 and other proteins from the promyelocytic leukemia nuclear bodies (NBs) form a large body that co-localizes with the HP1 signal. This is the first description of altered nuclear distribution of HP1 proteins in the constitutional ICF syndrome. Our results show that satellite DNA hypomethylation does not prevent HP1 proteins from associating with heterochromatin. They suggest that, at G2 phase, HP1 proteins are involved in the heterochromatin condensation and may therefore remain concentrated at these sites until the condensation is complete. They also indicate that proteins from the NB could play a role in this process. Finally, satellite DNA length polymorphism could affect the efficiency of heterochromatin condensation and thus contribute to the variability of the ICF phenotype.
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PMID:Subcellular distribution of HP1 proteins is altered in ICF syndrome. 1547 Mar 59

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive error of creatine synthesis characterized by cerebral creatine deficiency, accumulation of guanidinoacetate, mental retardation, epilepsy, and extrapyramidal symptoms. To date, 14 mutations of the GAMT gene in 27 patients have been reported. Mutation analysis was done using direct sequencing of PCR products and denaturing gradient gel electrophoresis in combination with direct sequencing. In contrast, we evaluated the efficiency of a newly developed DHPLC method to detect mutations in the GAMT gene by analysing DNA from 14 GAMT patients with known mutations. PCR amplification of both patient and control DNA was followed by formation of homoduplices and heteroduplices, and their detection by DHPLC. DHPLC identified all mutations tested and is the preferred choice of analytical method.
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PMID:Use of denaturing HPLC to provide efficient detection of mutations causing guanidinoacetate methyltransferase deficiency. 1605 53

A new patient affected by Guanidinoacetate methyltransferase (GAMT) deficiency was reported. This 13-year-old girl presented with mental retardation, as main symptom, associated with a typical pattern of biochemical and neurochemical (brain magnetic resonance spectroscopy) alterations. Molecular study detected a L197P transition on exon 6 of the GAMT gene. Since this mutation leaves the isoform B of the GAMT enzyme unaffected, the occurrence of biochemical alterations and disease in this subject testifies against the possibility that isoform b had GAMT activity.
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PMID:A mutation on exon 6 of guanidinoacetate methyltransferase (GAMT) gene supports a different function for isoform a and b of GAMT enzyme. 1629 31

Glutamate plays a central role in the excitatory synaptic transmission and is important for brain development and functioning. Increased glutamate levels in the synaptic cleft are related to neuronal damage associated with excitotoxicity. Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited neurometabolic disorder biochemically characterized by tissue accumulation of guanidinoacetate (GAA) and depletion of creatine. Affected patients present epilepsy and mental retardation whose pathogeny is unclear. In the present study we investigated the in vitro and in vivo (intrastriatal administration) effect of GAA on glutamate uptake by striatum slices of developing and adult rats. Results showed that GAA significantly inhibited in vitro glutamate uptake at 50 microM and 100 microM in all ages tested. We also tested the effect of taurine on the inhibition of glutamate uptake caused by GAA. Taurine significantly attenuated the inhibitory effect caused by 50 microM GAA, but did not alter that provoked by 100 microM GAA. Furthermore, intrastriatal administration of a solution of 30 microM GAA (0.06 nmol/striatum) significantly inhibited glutamate uptake by rat striatum slices. Our results suggest that the inhibition of striatal glutamate uptake caused by GAA might be involved in the neuropathology and especially in the acute neurological features present in patients with GAMT-deficiency.
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PMID:Guanidinoacetate inhibits glutamate uptake in rat striatum of rats at different ages. 1727 28


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