Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy

Several variants of the enzyme pyridox(am)ine 5′-phosphate oxidase (PNPO), responsible for a rare form of vitamin B<sub>6</sub>-dependent neonatal epileptic encephalopathy known as PNPO deficiency (PNPOD), have been reported. However, only a few of them have been characterised with respe...

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Autores principales:	Anna Barile, Philippa Mills, Martino L. di Salvo, Claudio Graziani, Victoria Bunik, Peter Clayton, Roberto Contestabile, Angela Tramonti
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	pyridox(am)ine 5′-phosphate oxidase pyridoxal 5′-phosphate neonatal epileptic encephalopathy PNPO deficiency Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/a79e06e8f164490eb7795b7699cbda64
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spelling	oai:doaj.org-article:a79e06e8f164490eb7795b7699cbda642021-11-11T17:25:40ZCharacterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy10.3390/ijms2221120131422-00671661-6596https://doaj.org/article/a79e06e8f164490eb7795b7699cbda642021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12013https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Several variants of the enzyme pyridox(am)ine 5′-phosphate oxidase (PNPO), responsible for a rare form of vitamin B<sub>6</sub>-dependent neonatal epileptic encephalopathy known as PNPO deficiency (PNPOD), have been reported. However, only a few of them have been characterised with respect to their structural and functional properties, despite the fact that the knowledge of how variants affect the enzyme may clarify the disease mechanism and improve treatment. Here, we report the characterisation of the catalytic, allosteric and structural properties of recombinantly expressed D33V, R161C, P213S, and E50K variants, among which D33V (present in approximately 10% of affected patients) is one of the more common variants responsible for PNPOD. The D33V and E50K variants have only mildly altered catalytic properties. In particular, the E50K variant, given that it has been found on the same chromosome with other known pathogenic variants, may be considered non-pathogenic. The P213S variant has lower thermal stability and reduced capability to bind the FMN cofactor. The variant involving Arg161 (R161C) largely decreases the affinity for the pyridoxine 5′-phosphate substrate and completely abolishes the allosteric feedback inhibition exerted by the pyridoxal 5′-phosphate product.Anna BarilePhilippa MillsMartino L. di SalvoClaudio GrazianiVictoria BunikPeter ClaytonRoberto ContestabileAngela TramontiMDPI AGarticlepyridox(am)ine 5′-phosphate oxidasepyridoxal 5′-phosphateneonatal epileptic encephalopathyPNPO deficiencyBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12013, p 12013 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pyridox(am)ine 5′-phosphate oxidase pyridoxal 5′-phosphate neonatal epileptic encephalopathy PNPO deficiency Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	pyridox(am)ine 5′-phosphate oxidase pyridoxal 5′-phosphate neonatal epileptic encephalopathy PNPO deficiency Biology (General) QH301-705.5 Chemistry QD1-999 Anna Barile Philippa Mills Martino L. di Salvo Claudio Graziani Victoria Bunik Peter Clayton Roberto Contestabile Angela Tramonti Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy
description	Several variants of the enzyme pyridox(am)ine 5′-phosphate oxidase (PNPO), responsible for a rare form of vitamin B<sub>6</sub>-dependent neonatal epileptic encephalopathy known as PNPO deficiency (PNPOD), have been reported. However, only a few of them have been characterised with respect to their structural and functional properties, despite the fact that the knowledge of how variants affect the enzyme may clarify the disease mechanism and improve treatment. Here, we report the characterisation of the catalytic, allosteric and structural properties of recombinantly expressed D33V, R161C, P213S, and E50K variants, among which D33V (present in approximately 10% of affected patients) is one of the more common variants responsible for PNPOD. The D33V and E50K variants have only mildly altered catalytic properties. In particular, the E50K variant, given that it has been found on the same chromosome with other known pathogenic variants, may be considered non-pathogenic. The P213S variant has lower thermal stability and reduced capability to bind the FMN cofactor. The variant involving Arg161 (R161C) largely decreases the affinity for the pyridoxine 5′-phosphate substrate and completely abolishes the allosteric feedback inhibition exerted by the pyridoxal 5′-phosphate product.
format	article
author	Anna Barile Philippa Mills Martino L. di Salvo Claudio Graziani Victoria Bunik Peter Clayton Roberto Contestabile Angela Tramonti
author_facet	Anna Barile Philippa Mills Martino L. di Salvo Claudio Graziani Victoria Bunik Peter Clayton Roberto Contestabile Angela Tramonti
author_sort	Anna Barile
title	Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy
title_short	Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy
title_full	Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy
title_fullStr	Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy
title_full_unstemmed	Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy
title_sort	characterization of novel pathogenic variants causing pyridox(am)ine 5′-phosphate oxidase-dependent epilepsy
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a79e06e8f164490eb7795b7699cbda64
work_keys_str_mv	AT annabarile characterizationofnovelpathogenicvariantscausingpyridoxamine5phosphateoxidasedependentepilepsy AT philippamills characterizationofnovelpathogenicvariantscausingpyridoxamine5phosphateoxidasedependentepilepsy AT martinoldisalvo characterizationofnovelpathogenicvariantscausingpyridoxamine5phosphateoxidasedependentepilepsy AT claudiograziani characterizationofnovelpathogenicvariantscausingpyridoxamine5phosphateoxidasedependentepilepsy AT victoriabunik characterizationofnovelpathogenicvariantscausingpyridoxamine5phosphateoxidasedependentepilepsy AT peterclayton characterizationofnovelpathogenicvariantscausingpyridoxamine5phosphateoxidasedependentepilepsy AT robertocontestabile characterizationofnovelpathogenicvariantscausingpyridoxamine5phosphateoxidasedependentepilepsy AT angelatramonti characterizationofnovelpathogenicvariantscausingpyridoxamine5phosphateoxidasedependentepilepsy
_version_	1718432137589293056

Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5′-Phosphate Oxidase-Dependent Epilepsy

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