PUBLICATION

PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights

Authors

Johnstone, D.L., Al-Shekaili, H.H., Tarailo-Graovac, M., Wolf, N.I., Ivy, A.S., Demarest, S., Roussel, Y., Ciapaite, J., van Roermund, C.W.T., Kernohan, K.D., Kosuta, C., Ban, K., Ito, Y., McBride, S., Al-Thihli, K., Abdelrahim, R.A., Koul, R., Al Futaisi, A., Haaxma, C.A., Olson, H., Sigurdardottir, L.Y., Arnold, G.L., Gerkes, E.H., Boon, M., Heiner-Fokkema, M.R., Noble, S., Bosma, M., Jans, J., Koolen, D.A., Kamsteeg, E.J., Drögemöller, B., Ross, C.J., Majewski, J., Cho, M.T., Begtrup, A., Wasserman, W.W., Bui, T., Brimble, E., Violante, S., Houten, S.M., Wevers, R.A., van Faassen, M., Kema, I.P., Lepage, N., Care4Rare Canada Consortium, Lines, M.A., Dyment, D.A., Wanders, R.J.A., Verhoeven-Duif, N., Ekker, M., Boycott, K.M., Friedman, J.M., Pena, I.A., van Karnebeek, C.D.M.

ID

ZDB-PUB-190123-4

Date

2019

Source

Brain : a journal of neurology 142(3): 542-559 (Journal)

Registered Authors

Ekker, Marc

Keywords

none

MeSH Terms

Animals
Disease Models, Animal
Epilepsy/etiology*
Epilepsy/physiopathology
Female
HEK293 Cells
Humans
Male
Phenotype
Proteins/genetics*
Proteins/metabolism*
Pyridoxal Phosphate/therapeutic use
Pyridoxine/deficiency
Vitamin B 6/metabolism
Vitamin B 6 Deficiency/genetics
Vitamin B 6 Deficiency/metabolism
Zebrafish

PubMed

30668673 Full text @ Brain

Abstract

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.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Mutations / Transgenics

Human Disease / Model

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Johnstone et al., 2019 ZDB-PUB-190123-4 PMID:30668673

PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights

Johnstone et al., 2019

ZDB-PUB-190123-4
PMID:30668673