PUBLICATION

Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia

Authors
Vaz, F.M., McDermott, J.H., Alders, M., Wortmann, S.B., Kölker, S., Pras-Raves, M.L., Vervaart, M.A.T., van Lenthe, H., Luyf, A.C.M., Elfrink, H.L., Metcalfe, K., Cuvertino, S., Clayton, P.E., Yarwood, R., Lowe, M.P., Lovell, S., Rogers, R.C., Deciphering Developmental Disorders Study, van Kampen, A.H.C., Ruiter, J.P.N., Wanders, R.J.A., Ferdinandusse, S., van Weeghel, M., Engelen, M., Banka, S.
ID
ZDB-PUB-191023-11
Date
2019
Source
Brain : a journal of neurology   142(11): 3382-3397 (Journal)
Registered Authors
Lowe, Martin
Keywords
CTP:phosphoethanolamine cytidylyltransferase, PCYT2, hereditary spastic paraplegia, lipidomics, phospholipid biosynthesis
MeSH Terms
  • Adolescent
  • Genetic Variation
  • Child
  • Male
  • Phosphatidylethanolamines/biosynthesis*
  • Humans
  • Gene Knockout Techniques
  • Epilepsy/genetics
  • Female
  • Atrophy
  • Brain/pathology
  • Zebrafish
  • Child, Preschool
  • Lipidomics
  • Developmental Disabilities/genetics
  • Spastic Paraplegia, Hereditary/genetics*
  • Alleles
  • Young Adult
  • Animals
  • Mice
  • RNA Nucleotidyltransferases/deficiency
  • RNA Nucleotidyltransferases/genetics*
(all 22)
PubMed
31637422 Full text @ Brain
Abstract
CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
No data available
Human Disease / Model
Human Disease Fish Conditions Evidence
hereditary spastic paraplegiaTAS
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Sequence Targeting Reagents
Target Reagent Reagent Type
pcyt2CRISPR1-pcyt2CRISPR
pcyt2CRISPR2-pcyt2CRISPR
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Fish
Antibodies
No data available
Orthology
No data available
Engineered Foreign Genes
No data available
Mapping
No data available