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

Brain. 2019 Nov 1;142(11):3382-3397. doi: 10.1093/brain/awz291.

Frédéric M Vaz ¹, John H McDermott ², Mariëlle Alders ³, Saskia B Wortmann ⁴ ⁵ ⁶, Stefan Kölker ⁷, Mia L Pras-Raves ¹ ⁸, Martin A T Vervaart ¹, Henk van Lenthe ¹, Angela C M Luyf ⁸, Hyung L Elfrink ¹, Kay Metcalfe ², Sara Cuvertino ⁹, Peter E Clayton ¹⁰, Rebecca Yarwood ¹¹, Martin P Lowe ¹¹, Simon Lovell ⁹, Richard C Rogers ¹², Deciphering Developmental Disorders Study, Antoine H C van Kampen ⁸ ¹³, Jos P N Ruiter ¹, Ronald J A Wanders ¹, Sacha Ferdinandusse ¹, Michel van Weeghel ¹, Marc Engelen ¹⁴, Siddharth Banka ² ⁹

Affiliations

1 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology and Metabolism, Meibergdreef 9, AZ Amsterdam, The Netherlands.
2 Manchester Centre for Genomics Medicine, St Mary's Hospital, Manchester University Hospital Foundation Trust, Health Innovation Manchester, Oxford Road, Manchester, UK.
3 Laboratory Genome Diagnostics, Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development, Meibergdreef 9, AZ Amsterdam, The Netherlands.
4 Institute of Human Genetics, Technical University München, Munich, Germany.
5 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
6 University Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
7 Division of Pediatric Neurology and Metabolic Medicine, Centre for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
8 Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health research institute, Amsterdam UMC, University of Amsterdam, Amsterdam AZ, The Netherlands.
9 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
10 Department of Pediatric Endocrinology, Royal Manchester Children's Hospital, Manchester University Hospital Foundation Trust, Oxford Road, Manchester, UK.
11 Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
12 Greenwood Genetic Center, 14 Edgewood Drive, Greenville, SC, USA.
13 Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, XH Amsterdam, The Netherlands.
14 Department of (Pediatric) Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands.

PMID: 31637422 DOI: 10.1093/brain/awz291

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.

Keywords

CTP:phosphoethanolamine cytidylyltransferase; PCYT2; hereditary spastic paraplegia; lipidomics; phospholipid biosynthesis.

Name
Email *

	Sorry, but the email address you supplied was invalid.