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

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...

Full description

Saved in:

Bibliographic Details
Published in:	Brain (London, England : 1878) Vol. 142; no. 11; pp. 3382 - 3397
Main Authors:	Vaz, Frédéric M, McDermott, John H, Alders, Mariëlle, Wortmann, Saskia B, Kölker, Stefan, Pras-Raves, Mia L, Vervaart, Martin A T, van Lenthe, Henk, Luyf, Angela C M, Elfrink, Hyung L, Metcalfe, Kay, Cuvertino, Sara, Clayton, Peter E, Yarwood, Rebecca, Lowe, Martin P, Lovell, Simon, Rogers, Richard C, van Kampen, Antoine H C, Ruiter, Jos P N, Wanders, Ronald J A, Ferdinandusse, Sacha, van Weeghel, Michel, Engelen, Marc, Banka, Siddharth
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 01-11-2019
Subjects:	Adolescent Alleles Animals Atrophy Brain - pathology Child Child, Preschool Developmental Disabilities - genetics Epilepsy - genetics Female Gene Knockout Techniques Genetic Variation Humans Lipidomics Male Mice Original Phosphatidylethanolamines - biosynthesis RNA Nucleotidyltransferases - deficiency RNA Nucleotidyltransferases - genetics Spastic Paraplegia, Hereditary - genetics Young Adult Zebrafish phospholipid biosynthesis PCYT2 CTP:phosphoethanolamine cytidylyltransferase hereditary spastic paraplegia lipidomics
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Frédéric M Vaz, John H. McDermott, Marc Engelen and Siddharth Banka authors contributed equally to this work.
ISSN:	0006-8950 1460-2156
DOI:	10.1093/brain/awz291