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David Valle - One of the best experts on this subject based on the ideXlab platform.
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Type II Hyperprolinemia Al-PYRROLINE-5-CARBOXYLIC ACID DEHYDROGENASE DEFICIENCY IN CULTURED SKIN FIBROBLASTS AND CIRCULATING LYMPHOCYTES
2016Co-Authors: David Valle, Stephen I. Goodman, Derek A. Applegarth, Vivian E. Shih, James M. PhangAbstract:abnormality in amino acid metabolism characterized by elevated plasma proline concentrations, iminoglycinuria. and the urinary excretion of A1-pyrroline compounds. To define the enzymologic defect of this biochemical dis-order, we developed a specific, sensitive radioisotopic assay for the proline degradative enzyme A'-pyrroline-5-carboxylic acid dehydrogenase. Using this assay, we have shown an absence of A'-pyrroline-5-carboxylic acid delhydrogenase activity in the cultured fibroblasts from three patients with type II Hyperprolinemia. \Ve con-firmed this result on cultured cells by demonstrating a similar absence of Al-pyrroline-5-carboxylic acid dehy-drogenase activity in extracts prepared from the periph-eral leukocytes of these patients. Additionally, we found significantly decreased levels of A'-pyrroline-5-carboxy-lic acid dehlvdrogenase activity in the leukocyte extracts from five obligate heterozygotes for type II hyperpro-linemia. We also demonstrated a reduction in leukocyte AL-pyrroline-5-carboxylic acid dehydrogenase activity in three successive generations of a family. A portion of this work was presented at the Annua
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Functional consequences of PRODH missense mutations.
American journal of human genetics, 2005Co-Authors: Hans-ulrich Bender, Wei Wen Lin, Shlomo Almashanu, Gary Steel, Alecia Willis, Ann E. Pulver, David ValleAbstract:PRODH maps to 22q11 in the region deleted in the velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS) and encodes proline oxidase (POX), a mitochondrial inner-membrane enzyme that catalyzes the first step in the proline degradation pathway. At least 16 PRODH missense mutations have been identified in studies of type I Hyperprolinemia (HPI) and schizophrenia, 10 of which are present at polymorphic frequencies. The functional consequences of these missense mutations have been inferred by evolutionary conservation, but none have been tested directly. Here, we report the effects of these mutations on POX activity. We find that four alleles (R185Q, L289M, A455S, and A472T) result in mild ( 70%) reduction in POX activity, whereas one (Q521R) increases POX activity. The POX encoded by one severe allele (T466M) shows in vitro responsiveness to high cofactor (flavin adenine dinucleotide) concentrations. Although there is limited information on plasma proline levels in individuals of known PRODH genotype, extant data suggest that severe Hyperprolinemia (>800 μM) occurs in individuals with large deletions and/or PRODH missense mutations with the most-severe effect on function (L441P and R453C), whereas modest Hyperprolinemia (300–500 μM) is associated with PRODH alleles with a moderate reduction in activity. Interestingly, three of the four alleles associated with or found in schizophrenia (V427M, L441P, and R453C) resulted in severe reduction of POX activity and Hyperprolinemia. These observations plus the high degree of polymorphism at the PRODH locus are consistent with the hypothesis that reduction in POX function is a risk factor for schizophrenia.
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Mutations in the ∆1-pyrroline 5-carboxylate dehydrogenase gene cause type II Hyperprolinemia
1998Co-Authors: Michael T. Geraghty, Wei Wen Lin, D. Vaughn, A. J. Nicholson, Gerardo Jimenez-sanchez, Ra Obie, M. P. Flynn, David ValleAbstract:We surveyed ∆1-pyrroline 5-carboxylate dehydro-genase genes from four patients with Hyperprolinemia type II using RT–PCR amplification, genomic PCR amplification and direct sequencing. We found four mutant alleles, two with frameshift mutations [A7fs(–1) and G521fs(+1)] and two with missense mutations (S352L and P16L). To test the functional consequences of three of these, we expressed them in a P5CDh-deficient strain of Saccharomyces cerevisiae. In contrast to wild-type human P5CDh, yeast expressing S352L and G521fs(+1) failed to grow on proline and had no detectable P5CDh activity. The P16L allele, however, produced fully functional P5CDh and subsequent analysis suggests that it is polymorphic in the relevant (Spanish) population. Interestingly, the G521fs(+1) allele segregates in the large Irish Traveller pedigree used to define the HPII phenotype. To our knowledge, this is the first description of the molecular basis for this inborn error
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cloning and characterization of cdnas encoding human proline oxidase the enzyme deficient in type i Hyperprolinemia 615
Pediatric Research, 1997Co-Authors: Wei Wen Lin, David ValleAbstract:Cloning and characterization of cDNAs encoding human proline oxidase, the enzyme deficient in type I Hyperprolinemia. † 615
James D Clelland - One of the best experts on this subject based on the ideXlab platform.
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evidence for association of Hyperprolinemia with schizophrenia and a measure of clinical outcome
Schizophrenia Research, 2011Co-Authors: Catherine L Clelland, Laura L Read, Amanda N Baraldi, Corinne P Bart, Carrie A Pappas, Laura Panek, Robert H Nadrich, James D ClellandAbstract:Abstract There are multiple genetic links between schizophrenia and a deficit of proline dehydrogenase (PRODH) enzyme activity. However, reports testing for an association of schizophrenia with the resulting proline elevation have been conflicting. The objectives of this study were to investigate whether Hyperprolinemia is associated with schizophrenia, and to measure the relationship between plasma proline, and clinical features and symptoms of schizophrenia. We performed a cross-sectional case–control study, comparing fasting plasma proline in 90 control subjects and 64 schizophrenic patients and testing for association of mild to moderate Hyperprolinemia with schizophrenia. As secondary analyses, the relationship between Hyperprolinemia and five measures of clinical onset, symptoms and outcome were investigated. Patients had significantly higher plasma proline than matched controls (p Mild to moderate Hyperprolinemia is a significant risk factor for schizophrenia, and may represent an intermediate phenotype in the disease. Hyperprolinemic patients have a significantly later age of first psychiatric hospitalization, suggestive of later onset, and hospital stays 46% longer than non-hyperprolinemic subjects. These findings have implications in the etiology of schizophrenia, and for the clinical management of these patients.
Eva Morava - One of the best experts on this subject based on the ideXlab platform.
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Long-term clinical outcome, therapy and mild mitochondrial dysfunction in Hyperprolinemia
Journal of Inherited Metabolic Disease, 2014Co-Authors: Thatjana Gardeitchik, Dorus Kouwenberg, Leo Kluijtmans, Ron Wevers, Eva MoravaAbstract:Although Hyperprolinemia type-II has a discriminative metabolic phenotype and is frequently associated with neurological system involvement, the casual relation between the metabolic abnormalities and the clinical features, except for those of the secondary B6 deficiency, has been frequently debated. In order to evaluate disease frequency and the neuro-metabolic outcome we searched our laboratory database between 1992 and 2010, including 20,991 urinary organic acid profiles. From these individuals 16,720 parallel blood samples were available, and were investigated by serum amino acid analysis. We also evaluated the clinical, neurological, psychological features, laboratory data and vitamin levels and therapeutic effect in metabolically confirmed Hyperprolinemia. Due to the mitochondrial localization of both ALDH4A1 and PRODH mitochondrial enzyme complex activity was evaluated and oxygen consumption was measured to assess ATP production in patient-fibroblasts. The Mitochondrial Disease Score was used to evaluate clinical mitochondrial dysfunction. The child behavior checklist was used to screen for psychopathology. We found four patients with increased urinary P5C diagnosed with Hyperprolinemia type II, and only one patient had Hyperprolinemia type I. All children with Hyperprolinemia type II had low normal B6 concentration, and three of the patients had biochemical markers suggesting mitochondrial dysfunction. Mitochondrial dysfunction was confirmed in a muscle biopsy in one case. Intellectual disability was found in two adolescent patients. All patients showed seizures and significant behavioral problems, including anxiety and hallucinations. The clinical course was non-progressive and independent from the B6 concentration and B6 therapy. Hyperprolinemia is a rare inborn error. Individuals with Hyperprolinemia should be monitored closely due to their frequent behavioral problems.
Valerie Walker - One of the best experts on this subject based on the ideXlab platform.
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a novel pyrroline 5 carboxylic acid and acetoacetic acid adduct in hyperprolinaemia type ii
Clinica Chimica Acta, 2003Co-Authors: Valerie Walker, Graham A Mills, John G Langley, John M. Mellor, Duncan R FarrantAbstract:Background: From investigations of a child with hyperprolinaemia type II, we demonstrated in vitro that pyridoxal phosphate forms a novel adduct with a proline metabolite, pyrroline-5-carboxylic acid, through Claisen condensation. Studies indicated that this was a previously unsuspected generic reaction of aldehydes and some ketones. We have subsequently found the acetoacetic acid adduct in both plasma and urine from the affected child. Methods: Mixtures of acetoacetic acid and pyrroline-5-carboxylic acid were co-incubated at pH 7.4 and 37 C, dried, or extracted and dried, derivatised and analysed by gas chromatography/mass spectrometry (GC/MS). Urine and plasma from the child were analysed. Results: Fourteen new peaks were found in derivatised pyrroline-5-carboxylic acid/acetoacetic acid co-incubates. From accurate molecular mass data, the four largest peaks were probably diastereoisomers of tri-trimethylsilyl (tri-TMS) derivatives of alcohol adducts formed by Claisen condensation. Eight other peaks were mono- and di-trimethylsilyl derivatives of the adduct and a decarboxylated product. The adduct was demonstrated unequivocally in the child's acute urine and traces in plasma. Conclusions: Pyrroline-5-carboxylic acid forms an adduct with acetoacetic acid, which was present in urine of a sick child with hyperprolinaemia type II. Evidence suggests it formed in vivo. The biological significance of this novel reaction of aldehydes and ketones merits investigation.
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pyridoxal phosphate de activation by pyrroline 5 carboxylic acid increased risk of vitamin b6 deficiency and seizures in Hyperprolinemia type ii
Journal of Biological Chemistry, 2001Co-Authors: R D Farrant, Valerie Walker, John M. Mellor, G A Mills, G LangleyAbstract:We previously identified vitamin B6 deficiency in a child presenting with seizures whose primary diagnosis was the inherited disorder Hyperprolinemia type II. This is an unrecognized association, which was not explained by diet or medication. We hypothesized that pyridoxal phosphate (vitamin B6 coenzyme) was de-activated by L-Delta(1)-pyrroline-5-carboxylic acid, the major intermediate that accumulates endogenously in Hyperprolinemia type II. The proposed interaction has now been investigated in vitro with high resolution 1H nuclear magnetic resonance spectroscopy and mass spectrometry at a pH of 7.4 and temperature of 310 K. Three novel adducts were identified. These were the result of a Claisen condensation (or Knoevenagel type of reaction) of the activated C-4 carbon of the pyrroline ring with the aldehyde carbon of pyridoxal phosphate. The structures of the adducts were confirmed by a combination of high performance liquid chromatography, nuclear magnetic resonance, and mass spectrometry. This interaction has not been reported before. From preliminary observations, pyrroline-5-carboxylic acid also condenses with other aromatic and aliphatic aldehydes and ketones, and this may be a previously unsuspected generic addition reaction. Pyrroline-5-carboxylic acid is thus found to be a unique endogenous vitamin antagonist. Vitamin B6 de-activation may contribute to seizures in Hyperprolinemia type II, which are so far unexplained, but they may be preventable with long term vitamin B6 supplementation.
John M. Mellor - One of the best experts on this subject based on the ideXlab platform.
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a novel pyrroline 5 carboxylic acid and acetoacetic acid adduct in hyperprolinaemia type ii
Clinica Chimica Acta, 2003Co-Authors: Valerie Walker, Graham A Mills, John G Langley, John M. Mellor, Duncan R FarrantAbstract:Background: From investigations of a child with hyperprolinaemia type II, we demonstrated in vitro that pyridoxal phosphate forms a novel adduct with a proline metabolite, pyrroline-5-carboxylic acid, through Claisen condensation. Studies indicated that this was a previously unsuspected generic reaction of aldehydes and some ketones. We have subsequently found the acetoacetic acid adduct in both plasma and urine from the affected child. Methods: Mixtures of acetoacetic acid and pyrroline-5-carboxylic acid were co-incubated at pH 7.4 and 37 C, dried, or extracted and dried, derivatised and analysed by gas chromatography/mass spectrometry (GC/MS). Urine and plasma from the child were analysed. Results: Fourteen new peaks were found in derivatised pyrroline-5-carboxylic acid/acetoacetic acid co-incubates. From accurate molecular mass data, the four largest peaks were probably diastereoisomers of tri-trimethylsilyl (tri-TMS) derivatives of alcohol adducts formed by Claisen condensation. Eight other peaks were mono- and di-trimethylsilyl derivatives of the adduct and a decarboxylated product. The adduct was demonstrated unequivocally in the child's acute urine and traces in plasma. Conclusions: Pyrroline-5-carboxylic acid forms an adduct with acetoacetic acid, which was present in urine of a sick child with hyperprolinaemia type II. Evidence suggests it formed in vivo. The biological significance of this novel reaction of aldehydes and ketones merits investigation.
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pyridoxal phosphate de activation by pyrroline 5 carboxylic acid increased risk of vitamin b6 deficiency and seizures in Hyperprolinemia type ii
Journal of Biological Chemistry, 2001Co-Authors: R D Farrant, Valerie Walker, John M. Mellor, G A Mills, G LangleyAbstract:We previously identified vitamin B6 deficiency in a child presenting with seizures whose primary diagnosis was the inherited disorder Hyperprolinemia type II. This is an unrecognized association, which was not explained by diet or medication. We hypothesized that pyridoxal phosphate (vitamin B6 coenzyme) was de-activated by L-Delta(1)-pyrroline-5-carboxylic acid, the major intermediate that accumulates endogenously in Hyperprolinemia type II. The proposed interaction has now been investigated in vitro with high resolution 1H nuclear magnetic resonance spectroscopy and mass spectrometry at a pH of 7.4 and temperature of 310 K. Three novel adducts were identified. These were the result of a Claisen condensation (or Knoevenagel type of reaction) of the activated C-4 carbon of the pyrroline ring with the aldehyde carbon of pyridoxal phosphate. The structures of the adducts were confirmed by a combination of high performance liquid chromatography, nuclear magnetic resonance, and mass spectrometry. This interaction has not been reported before. From preliminary observations, pyrroline-5-carboxylic acid also condenses with other aromatic and aliphatic aldehydes and ketones, and this may be a previously unsuspected generic addition reaction. Pyrroline-5-carboxylic acid is thus found to be a unique endogenous vitamin antagonist. Vitamin B6 de-activation may contribute to seizures in Hyperprolinemia type II, which are so far unexplained, but they may be preventable with long term vitamin B6 supplementation.