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

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

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

Prolidase deficiency is a rare, inherited disorder characterized by ulceration of the skin, mental retardation, and massive urinary excretion of imidodipeptides. Most patients also have recurrent infections, an unusual facial appearance, and splenomegaly. We describe a girl presenting with chronic dermatitis, recurrent respiratory tract infections since her first months of life, and facial features characteristic of prolidase deficiency. The diagnosis of prolidase deficiency was made at 4.5 months of age. The immunologic study in this patient showed an extreme and progressive increase of total immunoglobulin E (IgE) in serum (reaching the value of 77,600 IU/l) and defective chemotactic function of the neutrophils. Treatment with a hyper-proteic diet supplemented with ascorbic acid, manganese chlorite, and topical proline resulted in reduction of the frequency and severity of the infections and significant improvement of the skin lesions. The authors discuss the immunologic alterations and the favorable evolution with treatment in this patient.
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PMID:Prolidase deficiency with hyperimmunoglobulin E: a case report. 1200 Apr 88

Prolidase deficiency is an autosomal recessive inherited disease characterized clinically by frequent infections, mental retardation, and various skin lesions. Fundamental treatments for these manifestations have not been established. We performed adenovirus-mediated gene transfer of human prolidase cDNA into fibroblasts from patients with prolidase deficiency. Infection with the adenovirus vector carrying human prolidase cDNA increased prolidase activity in fibroblasts up to approximately 7.5 times of that of normal control fibroblasts. This indicates the feasibility of adenovirus-mediated gene therapy to treat patients with prolidase deficiency in the future.
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PMID:Amelioration of prolidase deficiency in fibroblasts using adenovirus mediated gene transfer. 1250 86

Prolidase deficiency (PD) is a rare autosomal recessive disorder characterized mainly by skin lesions of the legs and feet, mental retardation, and respiratory infections. Mutations at the PEPD locus, located on chromosome 19, are responsible for this disease. We identified a new PEPD allele in two unrelated Portuguese PD patients by analyses of reverse transcribed PCR-amplified cDNA. We used SSCP analysis of seven overlapping fragments spanning the entire coding region of the gene and detected abnormal SSCP bands in two of them: PD3 (nt 425-743) and PD4 (nt 661-973). Direct sequencing of the mutant cDNA and genomic DNA revealed a new homozygous 3-bp deletion (Y231del) in both cases. Transient expression in PD fibroblasts of wild-type and mutant prolidase cDNA confirmed reduced activity of the construct carrying the 3-bp deletion. The mutation results in a loss of prolidase activity in skin fibroblasts. Intracellular accumulation of Gly-Pro dipeptide in long-term cultured fibroblasts was detected by capillary electrophoresis. The mutation falls in the alpha2 domain of the "pita bread" structure proposed for E. coli and human prolidase by Bazan et al. on the bases of their sequence homology with E. coli methionine aminopeptidase. Taking into account the effects of the described mutations on stability and activity of the enzyme, we propose the identification of three different functional regions.
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PMID:Characterization of a new PEPD allele causing prolidase deficiency in two unrelated patients: natural-occurrent mutations as a tool to investigate structure-function relationship. 1530 82


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