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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.* ; Lovell, S.* ; Rogers, R.C.* ; van Kampen, A.H.C.* ; Ruiter, J.P.N.* ; Wanders, R.J.A.* ; Ferdinandusse, S.* ; van Weeghel, M.* ; Engelen, M.* ; Banka, S.*

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

Brain 142, 3382-3397 (2019)
Verlagsversion Forschungsdaten DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hereditary Spastic Paraplegia ; Pcyt2 ; Ctp:phosphoethanolamine Cytidylyltransferase ; Phospholipid Biosynthesis ; Lipidomics; Mass-spectrometry; Ctp; Plasmalogen; Phosphatidylethanolamine; Metabolism; Serine; Phosphatidylserine; Ethanolamine; Disorder; Defects
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Quellenangaben Band: 142, Heft: 11, Seiten: 3382-3397 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Begutachtungsstatus Peer reviewed