Associated with recessive, complicated HSP
The data in this study establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that maintaining balance in compounds called etherlipids is important for the development and function of the brain.
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.
SOURCE: Brain. 2019 Nov 1;142(11):3382-3397. doi: 10.1093/brain/awz291. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. PMID: 31637422
Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia.
Vaz FM1, McDermott JH2, Alders M3, Wortmann SB4,5,6, Kölker S7, Pras-Raves ML1,8, Vervaart MAT1, van Lenthe H1, Luyf ACM8, Elfrink HL1, Metcalfe K2, Cuvertino S9, Clayton PE10, Yarwood R11, Lowe MP11, Lovell S9, Rogers RC12; Deciphering Developmental Disorders Study, van Kampen AHC8,13, Ruiter JPN1, Wanders RJA1, Ferdinandusse S1, van Weeghel M1, Engelen M14, Banka S2,9.
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.