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)

Retarded body and brain growth and a deficit of myelin in the cerebral hemispheres and the cerebellum were observed in an animal model of phenylketonuria, the p-chlorophenylalanine and L-phenylalanine treated preweanling rat. These manifestations of phenylketonuria were reproduced in rats treated with phenylacetate in amounts approximating those likely to be produced in phenylketonuria. Young rats treated with equivalent amounts of other metabolites of phenylalanine, namely, phenylpyruvate, phenyllactate, and mandelate, which also accumulate in the brain during hyperphenylalaninemia, did not exhibit any toxic effects. Phenylpyruvate did not give rise to phenylacetate in the brain, but a small percentage was converted to phenyllactate. The gross composition of myelin isolated from the brains of saline and phenylacetate treated animals was similar. At various time intervals after subcutaneous injection, phenylacetate in the brain reached levels thirty times those of phenylpyruvate and phenyllactate, although animals received equivalent amounts of the three metabolites. The retarded growth of the body and brain of the young animal treated with phenylacetate may be attributed to the formation of phenylacetylcoenzyme A in the tissues. The site of action is very likely linked to acylcoenzyme A metabolism, i.e., the synthesis and utilization of acetylCoA and acetoacetylCoA, which are involved in reactions generating ATP and energy and in the synthesis of cholesterol and fatty acids. Results of this investigation indicate that growth retardation induced by phenylacetate during the period of very rapid development of the brain is responsible for the mental retardation in phenylketonuria.
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PMID:Myelin deficiency in experimental phenylketonuria: contribution of the aromatic acid metabolites of phenylalanine. 15 97

delta 1-pyrroline-5-carboxylate synthetase (P5CS) catalyzes the ATP and the NAD(P)H-dependent conversion of L-glutamate to glutamic gamma-semialdehyde (GSA) which is the metabolic precursor for proline biosynthesis. We cloned a human P5CS cDNA by database cloning strategy and sequenced 2,907 bp from this cDNA which has a closed open reading frame (ORF) of 2,385 bp coding for a polypeptide of 795 amino acid residues. This cDNA, as its plant counterpart, encodes a bifunctional enzyme, with both gamma-glutamyl kinase (gamma-GK) and gamma-glutamyl phosphate reductase (gamma-GPR) activities that catalyzes the first 2 steps in proline biosynthesis and it hybridizes to a 4.5 kb mRNA from various tissues. A human genetic disease caused by a deficient P5CS has been recognized. The phenotypic features for deficiency of P5CS include joint hyperlaxity, skin hyperelasticity, cataract and mental retardation with hyperammonemia and low plasma levels of proline, citrulline and ornithine.
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PMID:Database cloning human delta 1-pyrroline-5-carboxylate synthetase (P5CS) cDNA: a bifunctional enzyme catalyzing the first 2 steps in proline biosynthesis. 876 62

Williams syndrome (WS) is a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Hemizygosity of the elastin (ELN) gene can account for the vascular and connective tissue abnormalities observed in WS patients, but the genes that contribute to features such as infantile hypercalcemia, dysmorphic facies, and mental retardation remain to be identified. In addition, the size of the genomic interval commonly deleted in WS patients has not been established. In this study we report the characterization of a 500-kb region that was determined to be deleted in our collection of WS patients. A detailed physical map consisting of cosmid, P1 artificial chromosomes, and yeast artificial chromosomes was constructed and used for gene isolation experiments. Using the techniques of direct cDNA selection and genomic DNA sequencing, three known genes (ELN, LIMK1, and RFC2), a novel gene (WSCR1) with homology to RNA-binding proteins, a gene with homology to restin, and four other putative transcription units were identified. LIMK1 is a protein kinase with two repeats of the LIM/double zinc finger motif, and it is highly expressed in brain. RFC2 is the 40-kDa ATP-binding subunit of replication factor C, which is known to play a role in the elongation of DNA catalyzed by DNA polymerase delta and epsilon. LIMK1 and WSCR1 may be particularly relevant when explaining cognitive defects observed in WS patients.
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PMID:Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients. 881 60

We have cloned a novel serine/threonine protein kinase (PK428) which is highly related (65%) within the kinase domain to the myotonic dystrophy protein kinase (DM-PK), as well as the cyclic AMP-dependent protein kinase (33%). Northern blots demonstrate that PK428 mRNA is distributed widely among tissues and is expressed at the highest levels in pancreas, heart, and skeletal muscle, with lower levels in liver and lung. Two PK428 mRNAs 10 and 3.8 kilobase pairs in size are seen in a number of cell lines, including hematopoietic and breast cancer cells. An antibody generated to a glutathione S-transferase-PK428 fusion protein detects a 65-kDa protein in these cell lines, and a similarly sized protein when the cloned cDNA is transiently expressed in Cos 7 cells. Immunoprecipitation of the transiently expressed PK428 protein and incubation with [gamma-32P]ATP demonstrate that it is capable of autophosphorylation. In addition, immunoprecipitates of the PK428 protein kinase also phosphorylated histone H1 and a peptide encoding a cyclic AMP-dependent protein kinase substrate. The gene corresponding to the 3.8-kb PK428 mRNA, and its corresponding 65-kDa protein, was isolated by polymerase chain reaction screening of a P1 phage human genomic library. Using this P1 phage clone as a probe, the PK428 gene was located on 1q41-42, a possible location for a human senescence gene, a gene associated with Rippling muscle disease, as well as a region associated with genetically acquired mental retardation.
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PMID:Cloning and chromosomal location of a novel member of the myotonic dystrophy family of protein kinases. 909 43

delta 1-pyrroline 5-carboxylate synthetase (P5C synthetase) catalyzes the ATP and the NAD(P)H-dependent conversion of L-glutamate to glutamate semialdehyde (GSA) which is the metabolic precursor for proline biosynthesis. We described in two siblings a paradoxical hyperammonemia with hypoprolinemia and hypoornithinemia associated to bilateral cataract, mental retardation, joint laxity and skin hyperelasticity. We cloned human P5C synthetase-cDNA by database cloning strategy: this cDNA has an open reading frame of 2,385 bases coding for a polypeptide of 795 amino acids. Both patients are homozygous for an L396S substitution, this amino acid being highly conserved across species. This is the first report of a P5C synthetase deficiency in human.
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PMID:[A new inherited metabolic disease: delta1-pyrroline 5-carboxylate synthetase deficiency]. 962 38

Primary dystonias are movement disorders with dystonia as a major symptom. They are frequently inherited as Mendelian traits. There are at least eight clinically distinct autosomal dominant and two X-linked recessive forms. In addition, pedigree analyses suggest the occurrence of an autosomal recessive variant. The clinical classification is increasingly being replaced by a genetic one. To date gene loci have been identified in at least six autosomal dominant forms, i.e., in idiopathic torsion dystonia (9q34), focal dystonia (18p), adult-onset idiopathic torsion dystonia of mixed type (8p21-q22), dopa-responsive dystonia (14q22.1-q22.2), and paroxysmal dystonic choreoathetosis (2q25-q33; 1p21-p13.3). Gene loci in the X-linked recessive forms have been assigned to Xq13.1 in the X-linked dystonia parkinsonism syndrome and to Xq22 in X-linked sensorineural deafness, dystonia, and mental retardation. The disease genes have been identified in two autosomal dominant forms and in one X-linked recessive form. Mutations in a gene coding for an ATP-binding protein were detected in idiopathic torsion dystonia (DYT1), and the GTP cyclohydrolase 1 gene is mutated in dopa-responsive dystonia (DYT5). In sensorineural deafness, dystonia, and mental retardation, mutations were found in the gene DDP coding for a polypeptide of unknown function. This article reviews the clinical and molecular genetics of primary dystonias, critically discusses present findings, and proposes referring to the known forms, most of which can be distinguished by genetic criteria, as dystonias 1-12.
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PMID:Clinical and molecular genetics of primary dystonias. 1073 19

Phosphoglycerate kinase (PGK) catalyses the transfer of the acylphosphate group of 1,3-diphosphoglycerate to ADP with formation of 3-phosphoglycerate and ATP in the terminal stage of the glycolytic pathway. Two young brothers are presented who both experienced muscle pain, cramps and stiffness shortly after beginning heavy exercise. After these episodes they noticed that the urine was dark brown, indicating rhabdomyolysis and myoglobinuria. The neurological examinations were without remarks. There was no lactate increase in the ischaemic forearm exercise test. Both had very low PGK levels in muscle, erythrocytes, leukocytes and fibroblasts. This is the first family with more than one affected case of PGK deficiency and exercise-induced stiffness, myalgia and rhabdomyolysis. The clinical manifestations may resemble myophosphorylase deficiency (McArdle's disease: glycogenosis Type V) and muscle phosphofructokinase deficiency (Tarui's disease: glycogenosis Type VII). PGK deficiency is inherited as an X-linked trait and may show other features such as mental retardation and/or haemolytic anaemia.
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PMID:Phosphoglycerate kinase deficiency in two brothers with McArdle-like clinical symptoms. 1080 25

Maple syrup urine disease is caused by deficiency in the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. The clinical phenotype includes often fatal ketoacidosis, neurological derangement, and mental retardation. The type IA mutations Y393N-alpha, Y368C-alpha, and F364C-alpha, which occur in the E1alpha subunit of the decarboxylase (E1) component of the BCKD complex, impede the conversion of an alphabeta heterodimeric intermediate to a native alpha(2)beta(2) heterotetramer in the E1 assembly pathway. In the present study, we show that a natural osmolyte trimethylamine N-oxide (TMAO) at the optimal 1 m concentration restores E1 activity, up to 50% of the wild type, in the mutant E1 carrying the above missense mutations. TMAO promotes the conversion of otherwise trapped mutant heterodimers to active heterotetramers. This slow step does not involve dissociation/reassociation of the mutant heterodimers, which are preformed in the presence of chaperonins GroEL/GroES and Mg-ATP. The TMAO-stimulated mutant E1 activity is remarkably stable upon removal of the osmolyte, when cofactor thiamine pyrophosphate and the transacylase component of the BCKD complex are present. The above in vitro results offer the use of chemical chaperones such as TMAO as an approach to mitigate assembly defects caused by maple syrup urine disease mutations.
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PMID:Natural osmolyte trimethylamine N-oxide corrects assembly defects of mutant branched-chain alpha-ketoacid decarboxylase in maple syrup urine disease. 1150 2

Hyperactivity is a significant problem for almost all young males affected by fragile X syndrome (FXS), the most common inherited disease causing mental retardation. Therapeutical approaches are actually based on Central Nervous System (CNS) stimulants lacking a well defined rationale and efficacy while they further decrease the patient's limited attention span. A pilot study on 17 fragile X male treated with L-acetylcarnitine (LAC) over one year, showed a significant reduction of their hyperactivity behaviour tested by the Conners Abbreviated Parent-Teacher Questionnaire. LAC use in FXS patients derives from the hypothesis that the biochemical and physiological properties this substance has may preserve brain activity. LAC is a small, hydrosoluble molecule that easily diffuses in the extracellular space and enters any cell in the nervous system through specific transporters. Different cerebral areas use this molecule differently to metabolize glucose and lipids to provide for ATP and neurotrasmitters synthesis. The acetyl group LAC carriers represents a key metabolic signaling element possibly mediating its effect in the CNS. The exogenous administration of LAC may affect brain activity in FXS by: I) modulation of fuel partitioning for energy production, which at the mithocondrial level is associated with the Kreb's cycle metabolic role in neurotransmitter synthesis; II) remodelling of lipid membrane in terms of LAC actively determining the production of polyunsaturated fatty acids; III) preferential effect on the attention component of the cholinergic system which relies on its peculiar modality of communication in the CNS. Based on the above premises an explorative, double-blind, placebo controlled, multicenter study is ongoing. A total population of 160 children from nine European centers will be enrolled. The objective of this study is to determine the effect of LAC on the hyperactive behaviour of FXS children as evaluated by the administration of the Conners Abbreviated Parent Questionnaire.
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PMID:[L-acetylcarnitine treatment on fragile X patients hyperactive behaviour]. 1244 23

ATRX syndrome is characterized by X-linked mental retardation associated with alpha-thalassemia. The gene mutated in this disease, ATRX, encodes a plant homeodomain-like finger and a SWI2/SNF2-like ATPase motif, both of which are often found in chromatin-remodeling enzymes, but ATRX has not been characterized biochemically. By immunoprecipitation from HeLa extract, we found that ATRX is in a complex with transcription cofactor Daxx. The following evidence supports that ATRX and Daxx are components of an ATP-dependent chromatin-remodeling complex: (i) Daxx and ATRX can be coimmunoisolated by antibodies specific for each protein; (ii) a proportion of Daxx cofractionates with ATRX as a complex of 1 MDa by gel-filtration analysis; (iii) in extract from cells of a patient with ATRX syndrome, the level of the Daxx-ATRX complex is correspondingly reduced; (iv) a proportion of ATRX and Daxx colocalize in promyelocytic leukemia nuclear bodies, with which Daxx had previously been located; and (v) the ATRX complex displays ATP-dependent activities that resemble those of other chromatin-remodeling complexes, including triple-helix DNA displacement and alteration of mononucleosome disruption patterns. But unlike the previously described SWI/SNF or NURD complexes, the ATRX complex does not randomize DNA phasing of the mononucleosomes, suggesting that it may remodel chromatin differently. Taken together, the results suggest that ATRX functions in conjunction with Daxx in a novel chromatin-remodeling complex. The defects in ATRX syndrome may result from inappropriate expression of genes controlled by this complex.
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PMID:The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies. 1295 2


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