@article{discovery1522570,
          volume = {99},
            year = {2016},
           title = {Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin B6-Dependent Epilepsy},
          number = {6},
            note = {{\copyright} 2016 American Society of Human Genetics.This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at https://creativecommons.org/licenses/. Access may be initially restricted by the publisher.},
       publisher = {Elsevier (Cell Press)},
           month = {December},
           pages = {1325--1337},
         journal = {American Journal of Human Genetics},
            issn = {1537-6605},
          author = {Mills, PB and Darin, N and Reid, E and Prunetti, L and Samuelsson, L and Husain, RA and Wilson, M and El Yacoubi, B and Footitt, E and Chong, WK and Wilson, LC and Prunty, H and Pope, S and Lascelles, K and Champion, M and Wassmer, E and Veggiotti, P and de Crecy-Lagard, V and Clayton, PT},
             url = {http://dx.doi.org/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 which 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; by compounds accumulating as a result of inborn errors of other pathways or by ingested small molecules. Whole exome sequencing of 2 children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous
nonsense mutation in proline synthetase co-transcribed homolog (bacterial) (PROSC), a PLPbinding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified 4 additional children with biallelic PROSC mutations. Pretreatment 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 homologue ({\ensuremath{\Delta}}YggS) is pyridoxine-sensitive; complementation with human PROSC restored growth whilst hPROSC bearing p.Leu175Pro, p.Arg241Gln and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells - how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Whilst 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.}
}