title: Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease.
abstract: Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.
authors.affiliation: Metabolic Disease Group, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom;
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Koini
authors.initials: K
authors.lastname: Lim
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Amandine
authors.initials: A
authors.lastname: Girousse
authors.affiliation: Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Brown
authors.affiliation: Department of Cell Biology, School of Medicine, Yale University, New Haven, CT 06520;
authors.forename: Nora
authors.initials: N
authors.lastname: Kory
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Ann
authors.initials: A
authors.lastname: Robbins
authors.affiliation: Metabolic Disease Group, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom;
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Wolfson Brain Imaging Centre, University of Cambridge, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Alison
authors.initials: A
authors.lastname: Sleigh
authors.affiliation: Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Elaine
authors.initials: E
authors.lastname: Cochran
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Claire
authors.initials: C
authors.lastname: Adams
authors.affiliation: Moorfields Eye Hospital National Health Service Trust, London EC1V 2PD, United Kingdom; and.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Dev Borman
authors.affiliation: Centre for Endocrinology, Diabetes and Research, Royal Surrey County Hospital, Guildford GU2 7XX, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Russel-Jones
authors.affiliation: Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Phillip
authors.initials: P
authors.lastname: Gorden
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saudek
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; so104@medschl.cam.ac.uk ib1@sanger.ac.uk dbs23@medschl.cam.ac.uk.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: Department of Cell Biology, School of Medicine, Yale University, New Haven, CT 06520;
authors.forename: Tobias C
authors.initials: TC
authors.lastname: Walther
authors.affiliation: Metabolic Disease Group, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom;University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; so104@medschl.cam.ac.uk ib1@sanger.ac.uk dbs23@medschl.cam.ac.uk.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: University of Cambridge, Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; so104@medschl.cam.ac.uk ib1@sanger.ac.uk dbs23@medschl.cam.ac.uk.
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism; D000293:Adolescent; D000483:Alleles; D000818:Animals; D002648:Child; D008076:Cholesterol, HDL / Q000737:chemistry; D019916:Choline-Phosphate Cytidylyltransferase / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020404:Glycerophospholipids / Q000737:chemistry; D006801:Humans; D007328:Insulin / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008060:Lipodystrophy / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010641:Phenotype; D010713:Phosphatidylcholines / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D008076:Cholesterol, HDL; D020404:Glycerophospholipids; D007328:Insulin; D008055:Lipids; D010713:Phosphatidylcholines; D019916:Choline-Phosphate Cytidylyltransferase; C517213:PCYT1A protein, human; C500611:Pcyt1a protein, mouse