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)

Cultured skin fibroblasts or lymphoblastoid cells from eight patients with clinical symptoms of prolidase deficiency were analyzed in terms of enzyme activity, presence of material crossreacting with specific antibodies, biosynthesis of the polypeptide, and mRNA corresponding to the enzyme. There are at least two enzymes that hydrolyze imidodipeptides in these cells and these two enzymes could be separated by an immunochemical procedure. The specific assay for prolidase showed that the enzyme activity was virtually absent in six cell strains and was markedly reduced in two (less than 3% of controls). The activities of the labile enzyme that did not immunoprecipitate with the anti-prolidase antibody were decreased in the cells (30-60% of controls). Cell strains with residual activities of prolidase had immunological polypeptides crossreacting with a Mr 56,000, similar to findings in the normal enzyme. The polypeptide biosynthesis in these cells and the controls was similar. Northern blot analyses revealed the presence of mRNA in the polypeptide-positive cells, yet it was absent in the polypeptide-negative cells. The substrate specificities analyzed in the partially purified enzymes from the polypeptide-positive cell strains differed, presumably due to different mutations. Thus, there seems to be a molecular heterogeneity in prolidase deficiency. There was no apparent relation between the clinical symptoms and the biochemical phenotypes, except that mental retardation was present in the polypeptide-negative patients. The activities of the labile enzyme may not be a major factor in modifying the clinical symptoms.
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PMID:Biochemical basis of prolidase deficiency. Polypeptide and RNA phenotypes and the relation to clinical phenotypes. 168 67

Prolidase deficiency is an autosomal recessive disorder with highly variable symptoms, including mental retardation, skin lesions, and abnormalities of collagenous tissues. In Japanese female siblings with polypeptide negative prolidase deficiency, and with different degrees of severity of skin lesions, we noted an abnormal mRNA with skipping of 192 bp sequence corresponding to exon 14 in lymphoblastoid cells taken from these patients. Transfection and expression analyses using the mutant prolidase cDNA revealed that a mutant protein translated from the abnormal mRNA had an Mr of 49,000 and was enzymatically inactive. A 774-bp deletion, including exon 14 was noted in the prolidase gene. The deletion had termini within short, direct repeats ranging in size of 7 bp (CCACCCT). The "slipped mispairing" mechanism may predominate in the generation of the deletion at this locus. This mutation caused a 192-bp in-frame deletion of prolidase mRNA and was inherited from the consanguineous parents. The same mutation caused a different degree of clinical phenotype of prolidase deficiency in this family, therefore factor(s) not related to the PEPD gene product also contribute to development of the clinical symptoms. Identification of mutations in the PEPD gene from subjects with prolidase deficiency provides further insight into the physiological role and structure-function relationship of this biologically important enzyme.
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PMID:Molecular defect in siblings with prolidase deficiency and absence or presence of clinical symptoms. A 0.8-kb deletion with breakpoints at the short, direct repeat in the PEPD gene and synthesis of abnormal messenger RNA and inactive polypeptide. 201 May 34

Prolidase deficiency is an autosomal recessive disorder characterized by mental retardation and various skin lesions. Cultured skin fibroblasts were obtained from two independent patients with abnormal prolidase. Using the polymerase chain reaction, we amplified the entire coding region of human prolidase mRNA derived from patients' fibroblasts. Nucleotide sequence analysis of amplified cDNA products revealed a G to A substitution at position 826 in exon 12, where aspartic acid was replaced by asparagine at the amino acid residue 276, in cells from both patients. An analysis of the DNA showed that the substitution was homozygous. An expression plasmid clone containing a normal human prolidase cDNA (pEPD-W) or mutant prolidase cDNA (pEPD-M) was prepared, transfected, and tested for expression in NIH 3T3 cells. Incorporation of pEPD-W and pEPD-M resulted in the synthesis of an immunological polypeptide that corresponded to human prolidase. Active human enzyme was detected in cells transfected with pEPD-W, but not in those transfected with pEPD-M. These results were compatible with our observation of fibroblasts and confirmed that the substitution was responsible for the enzyme deficiency. As active prolidase was recovered in prolidase-deficient fibroblasts transfected with pEPD-W, this restoration of prolidase activity after transfection means that gene replacement therapy for individuals with this human disorder can be given due consideration.
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PMID:A single nucleotide change in the prolidase gene in fibroblasts from two patients with polypeptide positive prolidase deficiency. Expression of the mutant enzyme in NIH 3T3 cells. 236 24

Wilms' tumor is a childhood nephroblastoma that is postulated to arise through the inactivation of a tumor suppressor gene by a two-hit mechanism. A candidate 11p13 Wilms' tumor gene, WT1, has been cloned and shown to encode a zinc finger protein. Patients with the WAGR syndrome (Wilm's tumor, aniridia, genitourinary abnormalities, and mental retardation) have a high risk of developing Wilms' tumor and they carry constitutional deletions of one chromosome 11 allele encompassing the WT1 gene. Analysis of the remaining WT1 allele in a Wilms' tumor from a WAGR patient revealed the deletion of a single nucleotide in exon 7. This mutation likely played a key role in tumor formation, as it prevents translation of the DNA-binding zinc finger domain that is essential for the function of the WT1 polypeptide as a transcriptional regulator.
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PMID:Homozygous inactivation of WT1 in a Wilms' tumor associated with the WAGR syndrome. 768 65

Cystathionine beta-synthase (CBS) deficiency is the major cause of homocystinuria in humans. The most frequent symptoms of homocystinuria include: dislocated optic lenses, vascular disorders, skeletal abnormalities and mental retardation. Patients with this deficiency have elevated levels of homocyst(e)ine, methionine and low cysteine in their body fluids. These abnormal levels often partially or fully normalize upon treatment with pharmacological doses of vitamin B6. To investigate the molecular and biochemical basis for these conditions, it was necessary to determine the nucleotide and polypeptide sequence of CBS. We report here the human CBS cDNA sequence of 2,554 nucleotides encoding the CBS subunit of 551 amino acids. An intron of 214 bp appears to be retained in the 3'-untranslated region of most of the fibroblast and liver mRNA. We also report a frequent Mspl polymorphism in the 3'-untranslated sequence and two synonymous mutations in the coding region: 699C/T (Y233Y) and 1080C/T (A360A). The amino acid sequence similarity of human and rat CBS is greater than 90%; the enzyme also exhibits 52% similarity to O-acetylserine(thiol)-lyase from bacteria and plants. Lastly, we demonstrate that expression of the human enzyme in CHO cells yields enzymatically active protein of the expected size with a half-life of approximately 14 hrs.
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PMID:Human cystathionine beta-synthase cDNA: sequence, alternative splicing and expression in cultured cells. 790 80

Glycoprotein consist of oligosaccharides chains covalently attached to the polypeptide backbone. They are synthesized by two pathways; sugar nucleotide pathway and dolichol pathway. The degradation of glycoproteins occurs predominantly in the lysosomes through the ordered actions of lysosomal proteases, glycosidases, and aspartylglucosaminidase. Genetic deficiencies of these enzymes cause progressive accumulation of partially degraded oligosaccharides and glycopeptides, resulting in specific lysosomal storage diseases. Clinically, the diseases are characterized by the various degree of mental retardation, coarse facies, dysostosis multiplex, and visceromegaly. Although the urinary screening test for storage compounds is highly supportive, the definitive diagnosis of the disease is based on the measurement of lysosomal enzyme activity. This paper presents the review of clinical and biochemical features of this group of diseases including alpha-mannosidosis, beta-mannosidosis, fucosidosis, sialidosis, and aspartylglucosaminuria. Recent advances in molecular genetics in fucosidosis and aspartylglucosaminuria are also reviewed.
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PMID:[Disorders of glycoprotein degradation]. 857 45

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

Prolidase (E.C. 3.4.13.9) is a cytosolic exopeptidase that cleaves imidodipeptides and imidotripeptides with C-terminal proline or hydroxyproline. The enzyme apparently contributes to the conservation of iminoacids from endogenous and exogenous protein sources, mainly collagen. Prolidase plays an important role in the recycling of proline for collagen synthesis and cell growth and probably serves as an interface between protein nutrition and matrix breakdown. It seems that prolidase activity (despite the collagen gene expression) may be a step limiting factor in the regulation of collagen biosynthesis. The prolidase gene (PEPD) is located on chromosome 19 and encodes a polypeptide of 493 amino acids with molecular weight 54 kDa. The mature form of the enzyme is a dimer composed of two identical subunits. The gene harbors polymorphic alleles without effect on activity. Rare mutations found on exons 7,8,12 and 14 may be responsible for prolidase deficiency. Prolidase deficiency is characterized by massive imidodipeptiduria, skin lesions, recurrent infections, mental retardation and elevated proline-containing dipeptides in plasma. An effective treatment of the disease has not been identified.
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PMID:The role of prolidase as an enzyme participating in the metabolism of collagen. 902 May 26

Homocystinuria, due to a deficiency of the enzyme cystathionine beta-synthase (CBS), is an inborn error of sulphur-amino acid metabolism. This is an autosomal recessive disease which results in hyperhomocysteinaemia and a wide range of clinical features, including optic lens dislocation, mental retardation, skeletal abnormalities and premature thrombotic events. We report the identification of 5 missense mutations in the protein-coding region of the CBS gene from 3 patients with pyridoxine-nonresponsive homocystinuria. Reverse-transcription PCR was used to amplify CBS cDNA from each patient and the coding region was analysed by direct sequencing. The mutations detected included 3 novel (1058C-->T, 992C-->A and 1316G-->A) and 2 previously identified (430G-->A and 833C-->T) base alterations in the CBS cDNA. Each of these mutations predicts a single amino acid substitution in the CBS polypeptide. Appropriate cassettes of patient CBS cDNA, containing each of the above defined mutations, were used to replace the corresponding cassettes of normal CBS cDNA sequence within the bacterial expression vector pT7-7. These recombinant mutant and normal CBS constructs were expressed in Escherichia coli cells and the catalytic activities of the mutant proteins were compared with normal. All of the mutant proteins exhibited decreased catalytic activity in vitro, which confirmed the association between the individual mutation and CBS dysfunction in each patient.
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PMID:Characterisation of five missense mutations in the cystathionine beta-synthase gene from three patients with B6-nonresponsive homocystinuria. 915 16

a-Mannosidosis (MIM 248500) is an autosomal recessive lysosomal storage disorder resulting from deficient activity of lysosomal alpha-mannosidase (LAMAN) (EC 3.2.1.24). The disease is characterized by massive intracellular accumulation of mannose-rich oligosaccharides with resulting mental retardation, hearing loss, immune deficiency and skeletal changes. We report here the purification and characterization of human placenta LAMAN. The enzyme is synthesized as a single-chain precursor which is processed into three glycopeptides of 70, 42 and 15 kDa. The 70 kDa peptide is further partially proteolysed into three more peptides that are joined by disulfide bridges. The laman cDNA sequence was assembled from overlapping fragments obtained by PCR on human fibroblast and human lung cDNA. The deduced amino acid sequence contains a putative signal peptide of 48 amino acids followed by a polypeptide sequence of 962 amino acids. Northern blot analyses revealed a single transcript of approximately 3.5 kb present in all tissues examined but at varying levels. Two affected siblings of Palestinian origin were homozygous for a mutation that causes a His-->Leu replacement at a position which is conserved among class 2 alpha-mannosidases from several species.
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PMID:alpha-Mannosidosis: functional cloning of the lysosomal alpha-mannosidase cDNA and identification of a mutation in two affected siblings. 915 46


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