| Title |
Understanding pyrroline‐5‐carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure‐based analysis, and novel therapy with arginine
|
|---|---|
| Published in |
Journal of Inherited Metabolic Disease, December 2011
|
| DOI | 10.1007/s10545-011-9411-8 |
| Pubmed ID | |
| Authors |
Diego Martinelli, Johannes Häberle, Vicente Rubio, Cecilia Giunta, Ingrid Hausser, Rosalba Carrozzo, Nadine Gougeard, Clara Marco‐Marín, Bianca M. Goffredo, Maria Chiara Meschini, Elsa Bevivino, Sara Boenzi, Giovanna Stefania Colafati, Francesco Brancati, Matthias R. Baumgartner, Carlo Dionisi‐Vici |
| Abstract |
Δ(1)-Pyrroline-5-carboxylate synthetase (P5CS) catalyzes the first two steps of ornithine/proline biosynthesis. P5CS deficiency has been reported in three families, with patients presenting with cutis/joint laxity, cataracts, and neurodevelopmental delay. Only one family exhibited metabolic changes consistent with P5CS deficiency (low proline/ornithine/citrulline/arginine; fasting hyperammonemia). Here we report a new P5CS-deficient patient presenting the complete clinical/metabolic phenotype and carrying p.G93R and p.T299I substitutions in the γ-glutamyl kinase (γGK) component of P5CS. The effects of these substitutions are (1) tested in mutagenesis/functional studies with E.coli γGK, (2) rationalized by structural modelling, and (3) reflected in decreased P5CS protein in patient fibroblasts (shown by immunofluorescence). Using optical/electron microscopy on skin biopsy, we show collagen/elastin fiber alterations that may contribute to connective tissue laxity and are compatible with our angio-MRI finding of kinky brain vessels in the patient. MR spectroscopy revealed decreased brain creatine, which normalized after sustained arginine supplementation, with improvement of neurodevelopmental and metabolic parameters, suggesting a pathogenic role of brain creatine decrease and the value of arginine therapy. Morphological and functional studies of fibroblast mitochondria show that P5CS deficiency is not associated with the mitochondrial alterations observed in Δ(1)-pyrroline-5-carboxylate reductase deficiency (another proline biosynthesis defect presenting cutis laxa and neurological alterations). |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 44 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 44 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 10 | 23% |
| Student > Bachelor | 5 | 11% |
| Student > Master | 5 | 11% |
| Student > Ph. D. Student | 4 | 9% |
| Student > Doctoral Student | 3 | 7% |
| Other | 7 | 16% |
| Unknown | 10 | 23% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 14 | 32% |
| Biochemistry, Genetics and Molecular Biology | 11 | 25% |
| Agricultural and Biological Sciences | 5 | 11% |
| Nursing and Health Professions | 2 | 5% |
| Social Sciences | 1 | 2% |
| Other | 1 | 2% |
| Unknown | 10 | 23% |
Attention Score in Context
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#20,242,779
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Outputs from Journal of Inherited Metabolic Disease
#1,758
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#220,441
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Outputs of similar age from Journal of Inherited Metabolic Disease
#19
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