TY - JOUR
T1 - Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia
AU - Deciphering Developmental Disorders Study
AU - Vaz, Frédéric M.
AU - McDermott, John H.
AU - Alders, Mariëlle
AU - Wortmann, Saskia B.
AU - Kölker, Stefan
AU - Pras-Raves, Mia L.
AU - Vervaart, Martin A. T.
AU - van Lenthe, Henk
AU - Luyf, Angela C. M.
AU - Elfrink, Hyung L.
AU - Metcalfe, Kay
AU - Cuvertino, Sara
AU - Clayton, Peter E.
AU - Yarwood, Rebecca
AU - Lowe, Martin P.
AU - Lovell, Simon
AU - Rogers, Richard C.
AU - van Kampen, Antoine H. C.
AU - Ruiter, Jos P. N.
AU - Wanders, Ronald J. A.
AU - Ferdinandusse, Sacha
AU - van Weeghel, Michel
AU - Engelen, Marc
AU - Banka, Siddharth
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074308906&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/brain/awz291
DO - https://doi.org/10.1093/brain/awz291
M3 - Article
C2 - 31637422
SN - 0006-8950
VL - 142
SP - 3382
EP - 3397
JO - Brain
JF - Brain
IS - 11
ER -