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)

Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disease of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in hepatic tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5), a 454-amino acid protein encoded by a gene with 12 exons. To identify the causative mutations in five TAT alleles cloned from three RHS patients, chimeric genes constructed from normal and mutant TAT alleles were tested in directing TAT activity in a transient expression assay. DNA sequence analysis of the regions identified as nonfunctional revealed six different point mutations. Three RHS alleles have nonsense mutations at codons 57, 223, and 417, respectively. One "complex" RHS allele carries a GT----GG splice donor mutation in intron 8 together with a Gly----Val substitution at amino acid 362. A new splice acceptor site in intron 2 of the fifth RHS allele leads to a shift in reading frame.
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PMID:Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. 135 62

Nine patients with isovaleric acidemia were treated with a low-protein diet and supplemental glycine for up to 10 years. Carnitine was added to the therapy in four patients. Overall, the treatment was well tolerated, resulting in no significant side effects other than persistent hyperglycinemia. Normal growth was observed in all patients. Of four patients with the chronic phenotype, three, whose treatment was delayed beyond the first year of life, are mentally retarded. Two of five patients with the acute phenotype are retarded. The outcome in these two was complicated in one by neonatal intraventricular hemorrhage and in the other by therapeutic noncompliance. In our patients, only those who were treated successfully from early infancy and had no complications did not develop mental retardation. After initiation of therapy, there was a significant decrease in ketoacidotic attacks requiring hospitalization. Glycine is indicated for the treatment of acute ketoacidosis in these patients; none of the catastrophically ill newborn who received glycine died. The aim of treatment is to reduce the isovaleric acid burden to a minimum. Therapy consisting of leucine restriction with supplemental glycine and carniline should be started as soon as possible after birth.
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PMID:Isovaleric acidemia: medical and neurodevelopmental effects of long-term therapy. 338 30

To clarify the effects of perinatal anoxia on the subsequent amino acid metabolism in the brain of children, free amino acid levels in the cerebrospinal fluid (CSF) were determined in 15 children diagnosed as having cerebral palsy and/or mental retardation with perinatal anoxia, and 58 control children without anoxia, aged from 4 days to 12 yrs. There was no significant difference in total amino acid levels between anoxic children and the controls. In the controls, the Gln level in CSF was high, Arg, Asp and Glu levels in CSF were almost the same during infancy and childhood, and the levels of Orn, Lys, His, Tau, Thr, Ser, Asn, Gly, Ala, Val, Met, Ile, Leu, Tyr and Phe in CSF decreased with age until pre-school age. In the newborns and infants among the anoxic children, the levels of most free amino acids in CSF were relatively high compared with those of the controls and, except Glu and Gln, decreased with age during infancy. The Orn, His, Gly, Tyr and Phe levels in CSF of anoxic children were lower than those of the controls in older infants. These results suggest that perinatal anoxia affected free amino acid patterns in CSF of newborns and infants and that the subsequent disturbance of amino acid metabolism in their brains remained after birth.
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PMID:The effect of perinatal anoxia on amino acid metabolism in the developing brain. Part II: The effect of perinatal anoxia on the free amino acid patterns in CSF of infants and children. 406 76

Smith-Magenis syndrome (SMS) is a clinically recognizable multiple congenital anomaly/mental retardation syndrome associated with deletion of chromosome 17p11.2. Here we report the identification of a novel gene encoding a human microfibril-associated glycoprotein (MFAP4), which has been mapped to the SMS region. A full-length cDNA corresponding to this gene has been sequenced, and reveals a coding region of 255 amino acids. MFAP4 has a fibrinogen-like domain and shares a high level of sequence homology to a fragment of a bovine 36 kDa microfibril-associated glycoprotein. The N-terminus of the protein bears an Arg-Gly-Asp sequence that serves as the ligand motif for cell surface receptor integrin. These structural features of MFAP4 suggest that it is an extracellular matrix protein involved in cell adhesion or intercellular interactions. Deletion analysis has been conducted on 31 SMS patients by polymerase chain reaction and Southern analysis of somatic cell hybrids retaining the del(17)(p11.2) chromosome or by fluorescence in situ hybridization. The MFAP4 locus is deleted in 30 of 31 SMS patients. Thus, the function of this gene must be considered in the pathogenesis of SMS. Given our previous hypothesis that SMS is a contiguous gene syndrome, complete and exhaustive definition of the critical deletion interval and a thorough phenotype-genotype correlation is required to demonstrate the role and importance of the MFAP4 gene in SMS.
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PMID:The gene for a human microfibril-associated glycoprotein is commonly deleted in Smith-Magenis syndrome patients. 763 8

We have reported adhalin gene mutations in 4 patients from 3 families with malignant limb-girdle muscular dystrophy (MLGMD), and summarized the clinical features in adhalin-deficient muscular dystrophy (ADMD) reported as severe childhood autosomal recessive muscular dystrophy (SCARMD) in the English literatures. Adhalin cDNA amplified from RNA by reverse transcription polymerase chain reaction (RT-PCR) was sequenced in 3 patients from 2 consanguinous families (Wa. and Ta.) with MLGMD who showed immunohistochemically a complete deficiency of adhalin in the skeletal muscle, and adhalin genomic DNA amplified by PCR was sequenced in 1 patient from a non-consanguinous family (Ma.). In one patient from family Wa., a cytosine to thymine substitution at nt. 229 was identified in the adhalin gene, resulting in the replacement of Arg by Cys at codon 77. In two patients from family Ta., an adenine to guanine substitution at nt. 410 and an insertion of 15 bases between nt. 408 and 409 were identified, resulting in Glu to Gly replacement at codon 137 and insertion of a peptide with 5 amino acids. In one patient from family Ma., a deletion of adenine at nt. 404 or nt. 405 and a thymidine to cytosine substitution at nt. 470 were identified. These amino acid replacements are expected to change the secondary and tertiary structure, which may affect the interaction of adhalin with other dystrophin-associated glycoproteins and basal lamina, and may subsequently cause the degeneration of muscle fibers. Sixty-six cases from 49 families with ADMD have been reported in the literature. Compared with patients with Duchenne muscular dystrophy (DMD), patients with ADMD were older in age at the time of onset or loss of ambulation. Mental retardation and cardiac dysfunction were rarely observed in ADMD patients. On muscle histology, the number of necrotic fibers, opaque fibers and regenerative fibers was less in ADMD. ADMD was classified into two groups; complete and incomplete adhalin-deficient. There was no essential difference between the two groups in clinical features and muscle histology, but the former was characterized by more severe clinical features than the latter. ADMD can be caused by various types of mutations in the adhalin gene.
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PMID:[Adhalin gene mutations in malignant limb-girdle muscular dystrophy and clinical features in adhalin-deficient muscular dystrophy]. 874 43

The transcriptional silencing of the human gene, fragile X mental retardation 1 (FMR1), is due to abnormal methylation in response to an expanded 5'-untranslated CGG trinucleotide repeat and accounts for most cases of fragile X syndrome, a frequent inherited form of mental retardation. Although the encoded fragile X mental retardation protein (FMRP) is known to have properties of a RNA-binding protein, the precise function of FMRP remains to be elucidated. We report the cloning of the chicken homolog of FMR1 and show strong evolutionary conservation, with nucleotide and amino acid identities of 85 and 92%, respectively, between chicken and human. In place of the mammalian CGG trinucleotide repeat, a 99-nt tripartite repetitive element containing a CCT trinucleotide repeat flanked on both sides by dinucleotide repeats was identified. Blocks of highly conserved 3'-untranslated sequence were also found. Within the coding region, two copies each of the highly conserved K homology motif and the Arg-Gly-Gly (RGG) box motif, both ribonucleotide particle family domains implicated in RNA binding, were identified. Chicken FMRP was found to bind RNA in vitro, and this activity correlated with the presence of the carboxy-terminal portion of the protein that includes the RGG motifs.
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PMID:The chicken FMR1 gene is highly conserved with a CCT 5'-untranslated repeat and encodes an RNA-binding protein. 880 73

The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 A resolution. Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA metabolism in neurons, first identified using sera from cancer patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA). The structure of the third KH domain (KH3) of Nova-2 bound to a stem loop RNA resembles a molecular vise, with 5'-Ura-Cyt-Ade-Cyt-3' pinioned between an invariant Gly-X-X-Gly motif and the variable loop. Tetranucleotide recognition is supported by an aliphatic alpha helix/beta sheet RNA-binding platform, which mimics 5'-Ura-Gua-3' by making Watson-Crick-like hydrogen bonds with 5'-Cyt-Ade-3'. Sequence conservation suggests that fragile X mental retardation results from perturbation of RNA binding by the FMR1 protein.
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PMID:Sequence-specific RNA binding by a Nova KH domain: implications for paraneoplastic disease and the fragile X syndrome. 1067 14

GLUT1 deficiency is caused by a defect in the facilitative glucose transporter GLUT1. Impaired glucose transport across brain tissue barriers is reflected by hypoglycorrhachia and results in an epileptic encephalopathy with developmental delay and motor disorders. Recently heterozygous mutations in the GLUT1 gene (1p35-31.3) have been reported in sporadic patients. Parents and siblings carried the GLUT1 wild-type, suggesting a de novo, autosomal dominant condition resulting from GLUT1 haploinsufficiency. We report a father and two children from separate marriages affected by GLUT1 deficiency and carrying a novel heterozygous missense mutation (G272A) in the GLUT1 gene. Mutations were identified by polymerase chain reaction and DNA sequencing and confirmed by restriction fragment digest. The predicted amino acid change (Gly91Asp) affects an Arg-X-Gly-Arg-Arg motif between helices 2 and 3 that represents a cytoplasmic anchor point and is highly conserved among transporters of the major facilitator superfamily down to yeast and bacteria. GLUT1 immunoreactivity was normal, but 3-O-methyl-D-glucose uptake into erythrocytes was significantly reduced, suggesting a quantitatively normal, but functionally impaired, GLUT1 protein at the cell membrane. This is the first report of autosomal dominant transmission of GLUT1 deficiency, confirming that this condition is the result of haploinsufficiency. The Gly-->Asp mutation within a highly conserved sequence highlights its importance for GLUT1 function. GLUT1 deficiency should be considered in patients with epilepsy, mental retardation and motor disorders. Our observations have bearing on the identification of this treatable disorder in pediatric and adult patients, will modify current biochemical protocols which use parental controls and will enable genetic counseling of affected families.
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PMID:Autosomal dominant transmission of GLUT1 deficiency. 1113 15

Prolidase, a ubiquitously distributed dipeptidase, is involved in the latter stage of degradation of endogenous and dietary proteins and is particularly important in collagen catabolism. It hydrolyzes dipeptides containing proline or hydroxyproline at the C-terminal position. Mutations in the gene encoding for prolidase cause prolidase deficiency (PD), an autosomal recessive disorder mainly characterized by skin lesions, mental retardation and recurrent infectious. In this work we reported the identification of the molecular defect in five PD patients. Direct sequencing of PCR amplified genomic DNA showed a homozygous G>A transversion in two siblings leading to a G448R substitution. A heterozygous IVS11+1G>C transition causing the skipping of exon 11 and a null allele were detected in a third proband. In two unrelated patients, a homozygous IVS7-1G>A transversion was identified and shown to cause multiple alternative spliced transcripts. All the mutations result in loss of prolidase activity. Long-term cultured fibroblasts from these PD patients were used to develop an in vitro model that allowed investigation of the affected cells. Light and electron microscopy revealed that PD cells were more round and branched out than controls with increased cytosolic vacuolization, interruptions of the plasma membrane, mitochondria swelling, mitochondrial matrix and cristae modifications. JC-1 labeling showed decreased mitochondrial membrane potential. A significant intracellular accumulation of the Gly-Pro dipeptide was detected by capillary electrophoresis analysis. Our results provide the first evidence that absence of prolidase activity causes the activation of a necrosis-like cellular death, which could be responsible for the typical skin lesions in PD.
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PMID:Mutation analysis of five new patients affected by prolidase deficiency: the lack of enzyme activity causes necrosis-like cell death in cultured fibroblasts. 1238 72

To explore the hypothesis that L-phenylalanine (L-Phe) depresses glutamatergic synaptic transmission and thus contributes to brain dysfunction in phenylketonuria (PKU), the effects of L-Phe on spontaneous and miniature excitatory postsynaptic currents (s/mEPSCs) in rat and mouse hippocampal and cerebrocortical cultured neurons were studied using the patch-clamp technique. L-Phe depressed the amplitude and frequency of both N-methyl-D-aspartate (NMDA) and non-NMDA components of glutamate receptor (GluR) s/mEPSCs. The IC(50) of L-Phe to inhibit non-NMDAR mEPSC frequency was 0.98 +/- 0.13 mM, a brain concentration seen in classical PKU. In contrast, D-Phe had a significantly smaller effect, whereas L-leucine, an amino acid that competes with L-Phe for brain transporter, had no effect on mEPSCs. Unlike GluR s/mEPSCs, GABA receptor mIPSCs were not attenuated by L-Phe. A high extracellular concentration of glycine prevented the attenuation by L-Phe of NMDAR current, activated by exogenous agonist, and of NMDAR s/mEPSC amplitude, but not of NMDAR s/mEPSC frequency. On the other hand, L-Phe significantly depressed non-NMDAR current activated by low but not high concentrations of exogenous agonists. Glycine-independent attenuation of NMDAR s/mEPSC frequency suggests decreased presynaptic glutamate release caused by L-Phe, whereas decreased amplitudes of NMDAR and non-NMDAR s/mEPSCs are consistent with competition of L-Phe for the glycine- and glutamate-binding sites of NMDARs and non-NMDARs, respectively. The finding that GluR activity is significantly depressed at conditions characteristic of classical PKU indicates a potentially important contribution of impaired GluR function to PKU-related mental retardation and provides important insights into the potential physiological consequences of impaired GluR function.
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PMID:L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses. 1264 85


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