Journal of Inherited Metabolic Disease

, Volume 35, Issue 5, pp 761–776 | Cite as

Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine

  • 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
Original Article

Abstract

Δ1-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 Δ1-pyrroline-5-carboxylate reductase deficiency (another proline biosynthesis defect presenting cutis laxa and neurological alterations).

Notes

Acknowledgments

We thank the Association “la Vita è un Dono” for supporting the fellowship of Diego Martinelli, Isabel Pérez-Arellano for advice, and Enrique Pérez-Payá for help with CD analysis. This work was supported by grants BFU2008-05021 of the Spanish Ministry for Science (MEC and MICINN) and Prometeo/2009/051 of the Valencian Government.

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Copyright information

© SSIEM and Springer 2011

Authors and Affiliations

  • Diego Martinelli
    • 1
  • Johannes Häberle
    • 2
  • Vicente Rubio
    • 3
    • 4
  • Cecilia Giunta
    • 2
  • Ingrid Hausser
    • 5
  • Rosalba Carrozzo
    • 6
  • Nadine Gougeard
    • 3
    • 4
  • Clara Marco-Marín
    • 3
    • 4
  • Bianca M. Goffredo
    • 1
  • Maria Chiara Meschini
    • 6
  • Elsa Bevivino
    • 1
  • Sara Boenzi
    • 1
  • Giovanna Stefania Colafati
    • 7
  • Francesco Brancati
    • 8
  • Matthias R. Baumgartner
    • 2
  • Carlo Dionisi-Vici
    • 1
  1. 1.Division of MetabolismBambino Gesù Children’s HospitalRomeItaly
  2. 2.Division of Metabolism and Children’s Research Center (CRC)University Children’s Hospital ZurichZurichSwitzerland
  3. 3.Instituto de Biomedicina de Valencia (IBV-CSIC)ValenciaSpain
  4. 4.Centro de Investigación Biomédica en Red sobre Enfermedades Raras (CIBERER-ISCIII)ValenciaSpain
  5. 5.Electron Microscopic Laboratory, Dermatological Department and EM Core FacilityUniversity HeidelbergHeidelbergGermany
  6. 6.Division of Neuromuscular and Neurodegenerative DiseasesBambino Gesù Children’s HospitalRomeItaly
  7. 7.Divison of RadiologyBambino Gesù Children’s HospitalRomeItaly
  8. 8.Experimental Medicine and PathologyCSS-MendelRomeItaly

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