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

Artikel i vetenskaplig tidskrift
Författare Niklas Darin
Emma Reid
Laurence Prunetti
Lena Samuelsson
Ralf A Husain
Matthew Wilson
Basma El Yacoubi
Emma Footitt
W K Chong
Louise C Wilson
Helen Prunty
Simon Pope
Simon Heales
Karine Lascelles
Mike Champion
Evangeline Wassmer
Pierangelo Veggiotti
Valérie de Crécy-Lagard
Philippa B Mills
Peter T Clayton
Publicerad i American journal of human genetics
Volym 99
Nummer/häfte 6
Sidor 1325-1337
ISSN 1537-6605
Publiceringsår 2016
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för pediatrik
Sidor 1325-1337
Språk en
Länkar dx.doi.org/10.1016/j.ajhg.2016.10.0...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Klinisk medicin

Sammanfattning

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.

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