title: Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy.
abstract: Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.
authors.affiliation: Department of Pediatrics, University of Gothenburg and Sahlgrenska University Hospital, 41685 Gothenburg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Reid
authors.affiliation: Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Prunetti
authors.affiliation: Department of Clinical Genetics, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Samuelsson
authors.affiliation: Centre for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, 07740 Jena, Germany.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Husain
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Basma
authors.initials: B
authors.lastname: El Yacoubi
authors.affiliation: Department of Metabolic Medicine, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Footitt
authors.affiliation: Department of Radiology, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: W K
authors.initials: WK
authors.lastname: Chong
authors.affiliation: Department of Clinical Genetics, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Wilson
authors.affiliation: Department of Chemical Pathology, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Prunty
authors.affiliation: Neurometabolic Unit, National Hospital, Queen Square, London WC1N 3BG, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Pope
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK; Department of Chemical Pathology, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK; Neurometabolic Unit, National Hospital, Queen Square, London WC1N 3BG, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Heales
authors.affiliation: Department of Neuroscience, Evelina London Children's Hospital, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Karine
authors.initials: K
authors.lastname: Lascelles
authors.affiliation: Department of Inherited Metabolic Disease, Evelina London Children's Hospital, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Champion
authors.affiliation: Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK.
authors.forename: Evangeline
authors.initials: E
authors.lastname: Wassmer
authors.affiliation: Department of Child Neurology and Psychiatry, C. Mondino National Neurological Institute, Mondino 2, 27100 Pavia, Italy; Brain and Behaviour Department, University of Pavia, Strada Nuova, 65 Pavia, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Veggiotti
authors.affiliation: Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Valérie
authors.initials: V
authors.lastname: de Crécy-Lagard
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: p.mills@ucl.ac.uk.
authors.forename: Philippa B
authors.initials: PB
authors.lastname: Mills
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: peter.clayton@ucl.ac.uk.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Clayton
mesh_terms: D000293:Adolescent; D002336:Carnosine / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism*; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D006706:Homeostasis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D011392:Proline / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D011732:Pyridoxal Phosphate / Q000378:metabolism*; D025101:Vitamin B 6 / Q000097:blood / Q000378:metabolism*
chemical_list: C485670:PLPBP protein, human; D011506:Proteins; C005038:homocarnosine; D011732:Pyridoxal Phosphate; D025101:Vitamin B 6; D002336:Carnosine; D011392:Proline
keywords: PROSC; YggS; developmental delay; epilepsy; homeostasis; microcephaly; pyridoxal 5’-phosphate; pyridoxine; treatment; vitamin B6