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)

Prolidase deficiency is a rare autosomal recessive disorder characterized by iminodipeptiduria, severe skin ulcers, recurrent infections, and mental retardation. The enzyme prolidase hydrolyzes dipeptides containing C-terminal proline or hydroxyproline. We investigated the metabolic abnormality caused by prolidase deficiency in human cultured skin fibroblasts. These studies were undertaken to test biochemical hypotheses regarding the metabolic origins of the skin lesion occurring in this disease. Our results indicate that prolidase plays a major role in the recycling of dipeptide-bound proline. Control fibroblasts were able to use iminodipeptides in lieu of proline to sustain normal growth, whereas cells homozygous for the prolidase deficiency mutation were not. Proline derived from iminodipeptides diluted incorporation of radiolabeled extracellular proline into cellular protein in normal cells but not in mutant cells. Substitution of a prolidase-free medium for FCS did not affect the growth rate of control cell lines but increased the doubling time of prolidase-deficient cells by 19% (28% in the presence of iminodipeptides). Iminodipeptides added to control and mutant cells maintained in serum-free medium showed no adverse effects on protein synthesis. These results are consistent with a mechanism of biochemical pathology in which proline deprivation caused by the enzyme deficit is a primary cause of damage to skin cells. Prolidase regulation by product and substrate was studied. A 44% decrease in activity was observed in fibroblasts grown for 3 wk in proline-containing medium relative to proline-free medium. However, cells grown in medium in which iminodipeptides replaced proline showed no significant difference in prolidase activity.
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PMID:Prolidase deficiency in cultured human fibroblasts: biochemical pathology and iminodipeptide-enhanced growth. 143 3

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

Deficiency of prolidase is frequently associated with skin lesions and mental retardation. Biochemically, the condition is marked by iminodipeptiduria. We have investigated the feasibility of using donor erythrocytes to replace the deficient enzyme. Prolidase occurs in erythrocytes in an inactive form. If erythrocytes are incubated overnight at 37 degrees C in the presence of 1 mM MnCl2, the intracellular Mn++ concentration increases from 0.014 to 2.04 micrograms/ml. As a consequence, the activity of prolidase in hemolysates increases to 159 mumol glycyl-L-proline hydrolyzed/h/ml compared to 5 mumol/h/ml for hemolysates of cells incubated in the absence of Mn++. Hydrolysis of glycyl-L-proline by intact erythrocytes is reduced by the slow rate of iminodipeptide transport into the cell; however, intact cells hydrolyzed this substrate at a rate 10-20 times faster after preincubation with MnCl2. After exogenous MnCl2 is removed from the storage buffer, high levels of erythrocyte prolidase activity persist for at least 13 days. The kinetic parameters for intact activated erythrocyte-catalyzed hydrolysis of glycyl-L-proline have been estimated. These values predict that donor erythrocytes, activated with Mn++ before transfusion could play a significant role in the recovery of proline from dietary sources of iminodipeptides in patients with prolidase deficiency.
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PMID:In situ activation of human erythrocyte prolidase: potential for enzyme replacement therapy in prolidase deficiency. 320 27

Mutations at the PEPD locus cause prolidase deficiency (McKusick 170100), a rare autosomal recessive disorder characterized by iminodipeptiduria, skin ulcers, mental retardation, and recurrent infections. Four PEPD mutations from five severely affected individuals were characterized by analysis of reverse-transcribed, PCR-amplified (RT-PCR) cDNA. We used SSCP analysis on four overlapping cDNA fragments covering the entire coding region of the PEPD gene and detected abnormal SSCP bands for the fragment spanning all or part of exons 13-15 in three of the probands. Direct sequencing of the mutant cDNAs showed a G-->A, 1342 substitution (G448R) in two patients and a 3-bp deletion (delta E452 or delta E453) in another. In the other two probands the amplified products were of reduced size. Direct sequencing of these mutant cDNAs revealed a deletion of exon 5 in one patient and of exon 7 in the other. Intronic sequences flanking exons 5 and 7 were identified using inverse PCR followed by direct sequencing. Conventional PCR and direct sequencing then established the intron-exon borders of the mutant genomic DNA revealing two splice acceptor mutations: a G-->C substitution at position -1 of intron 4 and an A-->G substitution at position -2 of intron 6. Our results indicate that the severe form of prolidase deficiency is caused by multiple PEPD alleles. In this report we attempt to begin the process of describing these alleles and cataloging their phenotypic expression.
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PMID:Four novel PEPD alleles causing prolidase deficiency. 819 24

Prolidase deficiency is a rare hereditary disorder with a wide spectrum of clinical manifestations including skin ulcers, eczematous eruptions, characteristic facies, mental retardation, splenomegaly, and susceptibility to infections. We report two new cases of prolidase deficiency. Our patients had the typical manifestations of prolidase deficiency. One also had lupus erythematosus. Prolidase activity was either normal or half-normal in all family members. The skin disease in our patients did not respond to topical glycine/proline ointment or to oral vitamin C.
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PMID:Prolidase deficiency: a multisystemic hereditary disorder. 840 17

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

Deficiency of prolidase, a key enzyme in proline metabolism, is extremely rare and is usually associated with skin lesions, recurrent infections, characteristic facies, mental retardation, and splenomegaly. These clinical features are largely due to inhibition of normal recycling of proline, which causes an alteration in the metabolism of collagen and other proline-rich proteins. The case of a 25-year-old with all the recognized characteristics of prolidase deficiency is reported. Pathologic myopia, which has not been hitherto described in association with prolidase deficiency, is added to the clinical spectrum of this rare disorder.
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PMID:Prolidase deficiency associated with pathologic myopia. 958 29

We studied the pathogenetic role of iminodipeptides, and the effects of corticosteroids on the skin lesions of two adult female siblings with prolidase deficiency. The elder sister had had severe skin ulcers and mental retardation since childhood, while the younger sister had shown milder clinical manifestations since late adolescence. The ulcers showed vascular wall thickening and neutrophil infiltration. Oral prednisolone at moderate doses was not effective, but corticosteroid pulse therapy followed by a moderate dose of prednisolone improved the preulcerative indurated lesions and ulcers. A 2-year follow-up of the younger patient indicated that N-formyl methionyl leucyl phenylalanine-induced neutrophil superoxide generation was elevated, in parallel with an increase in the serum iminodipeptide level, when the skin ulcers and preulcerative indurated lesions were most active. Corticosteroid pulse therapy downregulated the superoxide generation by neutrophils. The serum iminodipeptide level, however, did not decrease during 25 days after pulse therapy. These findings suggest that iminodipeptides may play an important part in aggravating the skin lesions by priming neutrophil superoxide generation, and that high-dose corticosteroids improve the skin lesions, probably by inhibiting the infiltration, and superoxide generation by, neutrophils. Neutrophil superoxide generation was more prominent in the elder sister, suggesting that clinical severity may depend on the response of neutrophils to the iminodipeptides. Chronic stimulation by superoxide may cause thickening of cerebral blood vessels and eventual mental retardation.
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PMID:Corticosteroid treatment of prolidase deficiency skin lesions by inhibiting iminodipeptide-primed neutrophil superoxide generation. 1058 65


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