title: Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine.
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).
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, Piazza Sant'Onofrio, 4, 00165 Rome, Italy. diego.martinelli@opbg.net
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
authors.forename: Vicente
authors.initials: V
authors.lastname: Rubio
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.forename: Nadine
authors.initials: N
authors.lastname: Gougeard
authors.forename: Clara
authors.initials: C
authors.lastname: Marco-Marín
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Goffredo
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Meschini
authors.forename: Elsa
authors.initials: E
authors.lastname: Bevivino
authors.forename: Sara
authors.initials: S
authors.lastname: Boenzi
authors.forename: Giovanna Stefania
authors.initials: GS
authors.lastname: Colafati
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000201:enzymology / Q000378:metabolism / Q000628:therapy*; D000595:Amino Acid Sequence; D001120:Arginine / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009953:Ornithine-Oxo-Acid Transaminase / Q000172:deficiency* / Q000378:metabolism; D010641:Phenotype
chemical_list: D001120:Arginine; D009953:Ornithine-Oxo-Acid Transaminase