2. Academic Validation
  3. Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy

Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy

  • Am J Hum Genet. 2016 Dec 1;99(6):1325-1337. doi: 10.1016/j.ajhg.2016.10.011.
Niklas Darin 1,  Emma Reid 2,  Laurence Prunetti 3,  Lena Samuelsson 4,  Ralf A Husain 5,  Matthew Wilson 2,  Basma El Yacoubi 3,  Emma Footitt 6,  W K Chong 7,  Louise C Wilson 8,  Helen Prunty 9,  Simon Pope 10,  Simon Heales 11,  Karine Lascelles 12,  Mike Champion 13,  Evangeline Wassmer 14,  Pierangelo Veggiotti 15,  Valérie de Crécy-Lagard 3,  Philippa B Mills 16,  Peter T Clayton 17
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of Gothenburg and Sahlgrenska University Hospital, 41685 Gothenburg, Sweden.
  • 2 Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK.
  • 3 Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences and Genetic Institute, University of Florida, Gainesville, FL 32611, USA.
  • 4 Department of Clinical Genetics, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden.
  • 5 Centre for Inborn Metabolic Disorders, Department of Neuropediatrics, Jena University Hospital, 07740 Jena, Germany.
  • 6 Department of Metabolic Medicine, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
  • 7 Department of Radiology, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
  • 8 Department of Clinical Genetics, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
  • 9 Department of Chemical Pathology, Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, UK.
  • 10 Neurometabolic Unit, National Hospital, Queen Square, London WC1N 3BG, UK.
  • 11 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.
  • 12 Department of Neuroscience, Evelina London Children's Hospital, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
  • 13 Department of Inherited Metabolic Disease, Evelina London Children's Hospital, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
  • 14 Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK.
  • 15 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.
  • 16 Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: p.mills@ucl.ac.uk.
  • 17 Genetics and Genomic Medicine, UCL Institute of Child Health, London WC1N 1EH, UK. Electronic address: peter.clayton@ucl.ac.uk.
PMID: 27912044 DOI: 10.1016/j.ajhg.2016.10.011
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 B6 vitamer 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.

Keywords

PROSC; YggS; developmental delay; epilepsy; homeostasis; microcephaly; pyridoxal 5’-phosphate; pyridoxine; treatment; vitamin B6.

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