PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights
Rattachement africain : ca, rs, nl, us, om. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights
- Date Crossref
- 21/01/2019
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Ottawa Department of Biology pays non établi dans la noticeUniversité ou école supérieure
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Children's Hospital of Eastern Ontario pays non établi dans la noticeÉtablissement de santé
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University of British Columbia Department of Medical Genetics pays non établi dans la noticeUniversité ou école supérieure
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BC Children's Hospital pays non établi dans la noticeÉtablissement de santé
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BC Children's Hospital Research Institute pays non établi dans la noticeUniversité ou école supérieure
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University of Calgary pays non établi dans la noticeUniversité ou école supérieure
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Alberta Children's Hospital pays non établi dans la noticeÉtablissement de santé
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University of Belgrade pays non établi dans la noticeUniversité ou école supérieure
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Amsterdam Neuroscience pays non établi dans la noticeStructure de recherche
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Stanford University Department of Neurology and Neurological Sciences pays non établi dans la noticeUniversité ou école supérieure
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Children's Hospital Colorado pays non établi dans la noticeÉtablissement de santé
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University of Colorado Denver pays non établi dans la noticeUniversité ou école supérieure
Department of Biology — University of Ottawa, Children's Hospital of Eastern Ontario et Department of Medical Genetics — University of British Columbia, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.