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21 results on '"Elfrink, Hyung L."'

1. A conserved complex lipid signature marks human muscle aging and responds to short-term exercise

Author

Janssens, Georges E., Molenaars, Marte, Herzog, Katharina, Grevendonk, Lotte, Remie, Carlijn M. E., Vervaart, Martin A. T., Elfrink, Hyung L., Wever, Eric J. M., Schomakers, Bauke V., Denis, Simone W., Waterham, Hans R., Pras-Raves, Mia L., van Weeghel, Michel, van Kampen, Antoine H. C., Tammaro, Alessandra, Butter, Loes M., van der Rijt, Sanne, Florquin, Sandrine, Jongejan, Aldo, Moerland, Perry D., Hoeks, Joris, Schrauwen, Patrick, Vaz, Frédéric M., and Houtkooper, Riekelt H.

Published
2024
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2. A Targeted LC-MRM3 Proteomic Approach for the Diagnosis of SARS-CoV-2 Infection in Nasopharyngeal Swabs

Author

Drouin, Nicolas, Elfrink, Hyung L., Boers, Stefan A., van Hugten, Sam, Wessels, Els, de Vries, Jutte J.C., Groeneveld, Geert H., Miggiels, Paul, Van Puyvelde, Bart, Dhaenens, Maarten, Budding, Andries E., Ran, Leonie, Masius, Roy, Takats, Zoltan, Boogaerds, Arjen, Bulters, Markus, Muurlink, Wouter, Oostvogel, Paul, Harms, Amy C., van der Lubben, Mariken, and Hankemeier, Thomas

Published
2024
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5. Metabolomics and lipidomics in Caenorhabditis elegans using a single-sample preparation

Author

Molenaars, Marte, primary, Schomakers, Bauke V., additional, Elfrink, Hyung L., additional, Gao, Arwen W., additional, Vervaart, Martin A. T., additional, Pras-Raves, Mia L., additional, Luyf, Angela C., additional, Smith, Reuben L., additional, Sterken, Mark G., additional, Kammenga, Jan E., additional, van Kampen, Antoine H. C., additional, Janssens, Georges E., additional, Vaz, Frédéric M., additional, van Weeghel, Michel, additional, and Houtkooper, Riekelt H., additional

Published
2021
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6. Reduced nicotinamide mononucleotide is a new and potent NAD+precursor in mammalian cells and mice

Author

Zapata‐Pérez, Rubén, primary, Tammaro, Alessandra, additional, Schomakers, Bauke V., additional, Scantlebery, Angelique M. L., additional, Denis, Simone, additional, Elfrink, Hyung L., additional, Giroud‐Gerbetant, Judith, additional, Cantó, Carles, additional, López‐Leonardo, Carmen, additional, McIntyre, Rebecca L., additional, van Weeghel, Michel, additional, Sánchez‐Ferrer, Álvaro, additional, and Houtkooper, Riekelt H., additional

Published
2021
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7. The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes

Author

Welsink-Karssies, Mendy M., Weeghel, Michel van, Hollak, Carla E.M., Elfrink, Hyung L., Janssen, M.C.H., Lai, Kent, Vries, M.C. de, Ferdinandusse, Sacha, Bosch, Annet M., Welsink-Karssies, Mendy M., Weeghel, Michel van, Hollak, Carla E.M., Elfrink, Hyung L., Janssen, M.C.H., Lai, Kent, Vries, M.C. de, Ferdinandusse, Sacha, and Bosch, Annet M.

Abstract

Contains fulltext : 217662.pdf (Publisher’s version ) (Open Access)

Published
2020

8. Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

Author

Pathologie Pathologen staf, Cancer, Child Health, Genetica Klinische Genetica, Lezzerini, Marco, Penzo, Marianna, O'Donohue, Marie-Françoise, Marques Dos Santos Vieira, Carolina, Saby, Manon, Elfrink, Hyung L, Diets, Illja J, Hesse, Anne-Marie, Couté, Yohann, Gastou, Marc, Nin-Velez, Alexandra, Nikkels, Peter G J, Olson, Alexandra N, Zonneveld-Huijssoon, Evelien, Jongmans, Marjolijn C J, Zhang, GuangJun, van Weeghel, Michel, Houtkooper, Riekelt H, Wlodarski, Marcin W, Kuiper, Roland P, Bierings, Marc B, van der Werff Ten Bosch, Jutte, Leblanc, Thierry, Montanaro, Lorenzo, Dinman, Jonathan D, Da Costa, Lydie, Gleizes, Pierre-Emmanuel, MacInnes, Alyson W, Pathologie Pathologen staf, Cancer, Child Health, Genetica Klinische Genetica, Lezzerini, Marco, Penzo, Marianna, O'Donohue, Marie-Françoise, Marques Dos Santos Vieira, Carolina, Saby, Manon, Elfrink, Hyung L, Diets, Illja J, Hesse, Anne-Marie, Couté, Yohann, Gastou, Marc, Nin-Velez, Alexandra, Nikkels, Peter G J, Olson, Alexandra N, Zonneveld-Huijssoon, Evelien, Jongmans, Marjolijn C J, Zhang, GuangJun, van Weeghel, Michel, Houtkooper, Riekelt H, Wlodarski, Marcin W, Kuiper, Roland P, Bierings, Marc B, van der Werff Ten Bosch, Jutte, Leblanc, Thierry, Montanaro, Lorenzo, Dinman, Jonathan D, Da Costa, Lydie, Gleizes, Pierre-Emmanuel, and MacInnes, Alyson W

Published
2020

9. Author Reply to Peer Reviews of Metabolomics and lipidomics in C. elegans using a single sample preparation

Author

Houtkooper, Riekelt H., primary, van Weeghel, Michel, additional, Vaz, Frédéric M., additional, Janssens, Georges E., additional, van Kampen, Antoine H. C., additional, Kammenga, Jan E., additional, Sterken, Mark G., additional, Smith, Reuben L., additional, Luyf, Angela C., additional, Pras-Raves, Mia L., additional, Vervaart, Martin A.T., additional, Gao, Arwen W., additional, Elfrink, Hyung L., additional, Schomakers, Bauke V., additional, and Molenaars, Marte, additional

Published
2020
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11. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans

Author

Remie, Carlijn ME, primary, Roumans, Kay HM, additional, Moonen, Michiel PB, additional, Connell, Niels J, additional, Havekes, Bas, additional, Mevenkamp, Julian, additional, Lindeboom, Lucas, additional, de Wit, Vera HW, additional, van de Weijer, Tineke, additional, Aarts, Suzanne ABM, additional, Lutgens, Esther, additional, Schomakers, Bauke V, additional, Elfrink, Hyung L, additional, Zapata-Pérez, Rubén, additional, Houtkooper, Riekelt H, additional, Auwerx, Johan, additional, Hoeks, Joris, additional, Schrauwen-Hinderling, Vera B, additional, Phielix, Esther, additional, and Schrauwen, Patrick, additional

Published
2020
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12. Metabolomics and lipidomics in C. elegans using a single sample preparation

Author

Molenaars, Marte, primary, Schomakers, Bauke V., additional, Elfrink, Hyung L., additional, Gao, Arwen W., additional, Vervaart, Martin A.T., additional, Pras-Raves, Mia L., additional, Luyf, Angela C., additional, Smith, Reuben L., additional, Sterken, Mark G., additional, Kammenga, Jan E., additional, van Kampen, Antoine H. C., additional, Janssens, Georges E., additional, Vaz, Frédéric M., additional, van Weeghel, Michel, additional, and Houtkooper, Riekelt H., additional

Published
2020
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13. The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes

Author

Welsink-Karssies, Mendy M., primary, van Weeghel, Michel, additional, Hollak, Carla E.M., additional, Elfrink, Hyung L., additional, Janssen, Mirian C.H., additional, Lai, Kent, additional, Langendonk, Janneke G., additional, Oussoren, Esmee, additional, Ruiter, Jos P.N., additional, Treacy, Eileen P., additional, de Vries, Maaike, additional, Ferdinandusse, Sacha, additional, and Bosch, Annet M., additional

Published
2020
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14. Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

Author

Lezzerini, Marco, primary, Penzo, Marianna, additional, O’Donohue, Marie-Françoise, additional, Marques dos Santos Vieira, Carolina, additional, Saby, Manon, additional, Elfrink, Hyung L, additional, Diets, Illja J, additional, Hesse, Anne-Marie, additional, Couté, Yohann, additional, Gastou, Marc, additional, Nin-Velez, Alexandra, additional, Nikkels, Peter G J, additional, Olson, Alexandra N, additional, Zonneveld-Huijssoon, Evelien, additional, Jongmans, Marjolijn C J, additional, Zhang, GuangJun, additional, van Weeghel, Michel, additional, Houtkooper, Riekelt H, additional, Wlodarski, Marcin W, additional, Kuiper, Roland P, additional, Bierings, Marc B, additional, van der Werff ten Bosch, Jutte, additional, Leblanc, Thierry, additional, Montanaro, Lorenzo, additional, Dinman, Jonathan D, additional, Da Costa, Lydie, additional, Gleizes, Pierre-Emmanuel, additional, and MacInnes, Alyson W, additional

Published
2019
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15. Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism.

Author

Lezzerini, Marco, Penzo, Marianna, O'Donohue, Marie-Françoise, Marques dos Santos Vieira, Carolina, Saby, Manon, Elfrink, Hyung L, Diets, Illja J, Hesse, Anne-Marie, Couté, Yohann, Gastou, Marc, Nin-Velez, Alexandra, Nikkels, Peter G J, Olson, Alexandra N, Zonneveld-Huijssoon, Evelien, Jongmans, Marjolijn C J, Zhang, GuangJun, van Weeghel, Michel, Houtkooper, Riekelt H, Wlodarski, Marcin W, and Kuiper, Roland P

Published
2020
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16. Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia.

Author

Vaz, Frédéric M, McDermott, John H, Alders, Mariëlle, Wortmann, Saskia B, Kölker, Stefan, Pras-Raves, Mia L, Vervaart, Martin A T, Lenthe, Henk van, Luyf, Angela C M, Elfrink, Hyung L, Metcalfe, Kay, Cuvertino, Sara, Clayton, Peter E, Yarwood, Rebecca, Lowe, Martin P, Lovell, Simon, Rogers, Richard C, Study, Deciphering Developmental Disorders, Kampen, Antoine H C van, and Ruiter, Jos P N

Subjects
BIOSYNTHESIS, FAMILIAL spastic paraplegia, CEREBRAL atrophy, MEMBRANE lipids, NEURAL development, DEVELOPMENTAL delay
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. [ABSTRACT FROM AUTHOR]

Published
2019
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17. A targeted LC-MRM3proteomic approach for the diagnosis of SARS-CoV-2 infection in nasopharyngeal swabs

Author

Drouin, Nicolas, Elfrink, Hyung L., Boers, Stefan A., van Hugten, Sam, Wessels, Els, de Vries, Jutte J.C., Groeneveld, Geert H., Miggiels, Paul, Van Puyvelde, Bart, Dhaenens, Maarten, Budding, Andries E., Ran, Leonie, Masius, Roy, Takats, Zoltan, Boogaerds, Arjen, Bulters, Markus, Muurlink, Wouter, Oostvogel, Paul, Harms, Amy C., van der Lubben, Mariken, and Hankemeier, Thomas

Abstract

Since its first appearance, SARS-CoV-2 quickly spread around the world and the lack of adequate PCR testing capacities, especially during the early pandemic, led the scientific community to explore new approaches such as mass spectrometry (MS).

Published
2024
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19. Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

Author

Marianna Penzo, Riekelt H. Houtkooper, Marjolijn C.J. Jongmans, Alexandra Nin-Velez, Carolina Marques dos Santos Vieira, Evelien Zonneveld-Huijssoon, Alexandra N. Olson, Roland P. Kuiper, Anne-Marie Hesse, Marie-Françoise O'Donohue, Marc Bierings, Hyung L. Elfrink, Michel van Weeghel, Marco Lezzerini, Manon Saby, Peter G. J. Nikkels, Alyson W. MacInnes, Lydie Da Costa, Illja J. Diets, Pierre-Emmanuel Gleizes, Jonathan D. Dinman, Marc Gastou, Lorenzo Montanaro, Yohann Couté, Thierry Leblanc, GuangJun Zhang, Marcin W. Wlodarski, Jutte van der Werff ten Bosch, Lezzerini, Marco, Penzo, Marianna, O'Donohue, Marie-Françoise, Marques Dos Santos Vieira, Carolina, Saby, Manon, Elfrink, Hyung L, Diets, Illja J, Hesse, Anne-Marie, Couté, Yohann, Gastou, Marc, Nin-Velez, Alexandra, Nikkels, Peter G J, Olson, Alexandra N, Zonneveld-Huijssoon, Evelien, Jongmans, Marjolijn C J, Zhang, GuangJun, van Weeghel, Michel, Houtkooper, Riekelt H, Wlodarski, Marcin W, Kuiper, Roland P, Bierings, Marc B, van der Werff Ten Bosch, Jutte, Leblanc, Thierry, Montanaro, Lorenzo, Dinman, Jonathan D, Da Costa, Lydie, Gleizes, Pierre-Emmanuel, MacInnes, Alyson W, Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), The Beatson Institute for Cancer Research, University of Glasgow, Human Genetics, Radboud University Medical Center [Nijmegen], Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Laboratoire de biologie moléculaire eucaryote (LBME), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), ANR-15-CE12-0001,DBA-MULTIGENES,DBA-MULTIGENES: identification et caractérisation de gènes candidats pour la découverte de nouveaux mécanismes physiopathologiques à l'origine de l'anémie de Blackfan-Diamond.(2015), Laboratory Genetic Metabolic Diseases, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, APH - Aging & Later Life, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Clinical sciences, Growth and Development, and Pediatrics

Subjects
Male, INTELLECTUAL DISABILITY, Ribosomopathy, [SDV]Life Sciences [q-bio], Ribosome biogenesis, medicine.disease_cause, Ribosome, PATHWAY, 0302 clinical medicine, RPL9, diamond blackfan anemia, DBA, ribosomes, ribosomopathy, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], RNA Precursors, Missense mutation, FAILURE, ASSAY, Variants in ribosomal protein, RNA Processing, Post-Transcriptional, Child, Cancer, Anemia, Diamond-Blackfan, Medicine(all), Genetics, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, Mutation, ABNORMALITIES, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, 3. Good health, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Female, Eukaryotic Ribosome, Adult, Ribosomal Proteins, Adolescent, DATABASE, DIAMOND-BLACKFAN ANEMIA, Biology, bone marrow failure syndrome, 03 medical and health sciences, Erythroid Cells, Ribosomal protein, Exome Sequencing, medicine, Humans, RNA, Messenger, Gene, Molecular Biology, 030304 developmental biology, PREDISPOSITION, MODEL, Genes, Cellular Metabolism, 5' Untranslated Regions, Ribosomes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Contains fulltext : 218593.pdf (Publisher’s version ) (Open Access) Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5'UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5'UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5'UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.

Published
2020

20. Reduced nicotinamide mononucleotide is a new and potent NAD + precursor in mammalian cells and mice.

Author

Zapata-Pérez R, Tammaro A, Schomakers BV, Scantlebery AML, Denis S, Elfrink HL, Giroud-Gerbetant J, Cantó C, López-Leonardo C, McIntyre RL, van Weeghel M, Sánchez-Ferrer Á, and Houtkooper RH

Subjects
Animals, Cell Line, Cell Survival, Epithelial Cells drug effects, Homeostasis, Humans, Kidney Tubules, Male, Mice, Mice, Inbred C57BL, Molecular Structure, NAD genetics, Nicotinamide Mononucleotide chemistry, Reperfusion Injury, NAD metabolism, Nicotinamide Mononucleotide metabolism
Abstract

Nicotinamide adenine dinucleotide (NAD + ) homeostasis is constantly compromised due to degradation by NAD + -dependent enzymes. NAD + replenishment by supplementation with the NAD + precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) can alleviate this imbalance. However, NMN and NR are limited by their mild effect on the cellular NAD + pool and the need of high doses. Here, we report a synthesis method of a reduced form of NMN (NMNH), and identify this molecule as a new NAD + precursor for the first time. We show that NMNH increases NAD + levels to a much higher extent and faster than NMN or NR, and that it is metabolized through a different, NRK and NAMPT-independent, pathway. We also demonstrate that NMNH reduces damage and accelerates repair in renal tubular epithelial cells upon hypoxia/reoxygenation injury. Finally, we find that NMNH administration in mice causes a rapid and sustained NAD + surge in whole blood, which is accompanied by increased NAD + levels in liver, kidney, muscle, brain, brown adipose tissue, and heart, but not in white adipose tissue. Together, our data highlight NMNH as a new NAD + precursor with therapeutic potential for acute kidney injury, confirm the existence of a novel pathway for the recycling of reduced NAD + precursors and establish NMNH as a member of the new family of reduced NAD + precursors., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Published
2021
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21. Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia.

Author

Vaz FM, McDermott JH, Alders M, Wortmann SB, Kölker S, Pras-Raves ML, Vervaart MAT, van Lenthe H, Luyf ACM, Elfrink HL, Metcalfe K, Cuvertino S, Clayton PE, Yarwood R, Lowe MP, Lovell S, Rogers RC, van Kampen AHC, Ruiter JPN, Wanders RJA, Ferdinandusse S, van Weeghel M, Engelen M, and Banka S

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, RNA Nucleotidyltransferases deficiency, Young Adult, Zebrafish, Phosphatidylethanolamines biosynthesis, RNA Nucleotidyltransferases genetics, Spastic Paraplegia, Hereditary genetics
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., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2019
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