Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
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

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.
 ...
PMID:Four novel PEPD alleles causing prolidase deficiency. 819 24

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.
 ...
PMID:The role of prolidase as an enzyme participating in the metabolism of collagen. 902 May 26

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.
 ...
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

Prolidase deficiency (PD) is a rare autosomal recessive connective tissue disorder caused by mutations in the prolidase gene. The PD patients show a wide range of clinical outcomes characterised mainly by intractable skin ulcers, mental retardation and recurrent respiratory infections. Here we describe five different PEPD mutations in six European patients. We identified two new PEPD mutant alleles: a 13 bp duplication in exon 8, which is the first reported duplication in the prolidase gene and a point mutation resulting in a change in amino acid E412, a highly conserved residue among different species. The E412K substitution is responsible for the first reported phenotypic variability within a family with severe and asymptomatic outcomes.
 ...
PMID:Molecular characterisation of six patients with prolidase deficiency: identification of the first small duplication in the prolidase gene and of a mutation generating symptomatic and asymptomatic outcomes within the same family. 1714 20

Prolidase deficiency (PD) is a rare recessive disorder resulting from mutations in the prolidase gene (PEPD); only 17 causative mutant alleles had been so far characterized. Prolidase is a ubiquitous enzyme that hydrolyses dipeptides with C-terminal proline or hydroxyproline residues and indeed, lack of this enzyme activity causes massive urine excretion of undigested iminodipeptides. The clinical manifestations of PD are widely variable, and include intractable skin ulcers, unusual face, different degree of mental retardation, and recurrent infections. No definitive treatment is at present available.We report an 8-year girl with a typical PD facies, normal intelligence, and recurrent deep ulcerations complicated by infections. She was found to be compound heterozygous for two novel mutations in PEPD, c.1133delACG and c.1301delT, affecting the C-terminal end of the enzyme where the active site is located. Given her life-threatening course, she underwent allogeneic hematopoietic stem cell transplantation (HSCT) from her HLA-identical brother, confirmed heterozygous for the c.1133delACG allele. Successful engraftment was documented by full-donor chimerism. Posttransplant monitoring of erythrocyte prolidase activity showed that the child had converted to a heterozygous pattern. Reduction of excreted urine dipeptides, evaluated by capillary electrophoresis, supported the effectiveness of the treatment. Unfortunately the patient died on day +92 of invasive fungal infection.Despite the unfavorable outcome, we provide the first evidence that HSCT has the potential to reverse some of the biochemical features of PD patients. The indication to transplant must be balanced against the clinical manifestation of individual patients.
 ...
PMID:Partial Rescue of Biochemical Parameters After Hematopoietic Stem Cell Transplantation in a Patient with Prolidase Deficiency Due to Two Novel PEPD Mutations. 2343 Aug 76

Prolidase gene (PEPD) encodes prolidase enzyme, which is responsible for hydrolysis of dipeptides containing proline or hydroxyproline at their C-terminal end. Mutations in PEPD gene cause, in human, prolidase deficiency (PD), a rare autosomal recessive disorder. PD patients show reduced or absent prolidase activity and a broad spectrum of phenotypic traits including various degrees of mental retardation. This is the first report correlating PD and brain damages using as a model system prolidase deficient mice, the so called dark-like (dal) mutant mice. We focused our attention on dal postnatal brain development, revealing a panel of different morphological defects in the cerebral and cerebellar cortices, such as undulations of the cerebral cortex, cell rarefaction, defects in cerebellar cortex lobulation, and blood vessels overgrowth. These anomalies might be ascribed to altered angiogenic process and loss of pial basement membrane integrity. Further studies will be directed to find a correlation between neuroarchitecture alterations and functional consequences.
...
PMID:Brain morphological defects in prolidase deficient mice: first report. 2530 48

Prolidase is a metallopeptidase that cleaves iminodipeptides containing a proline (Pro) or hydroxyproline (Hyp) residue at their C-terminal end. The disease prolidase deficiency (PD) is a rare recessive human disorder characterized by reduced prolidase activity. PD manifests itself by a wide range of severe clinical symptoms, most commonly as skin ulceration, recurrent infections of the respiratory tract, and mental retardation. Several mutations in the PEPD gene have been identified that are responsible for the loss or the reduction of prolidase activity. In contrast, the structural basis of enzyme inactivation has so far remained elusive. In this study, we present high resolution crystal structures of a number of human prolidase (HsProl) variants, in which single amino acids are either substituted by others or deleted. The observed implications of the mutations on the three-dimensional structure of HsProl are reported and discussed and related to their enzymatic activity. The resulting structures may be divided into four groups depending on the presumed effect of the corresponding mutations on the reaction mechanism. The four possible inactivation mechanisms, which could be elucidated, are disruption of the catalytic Mn2 (OH- )-center, introduction of chain disorder along with the displacement of important active site residues, rigidification of the active site, and flexibilization of the active site.
 ...
PMID:Structural basis for prolidase deficiency disease mechanisms. 3006 4