title: Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function.
abstract: OBJECTIVE
  The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).
  
  
  OBJECTIVE
  To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.
  
  
  METHODS
  Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants.
  
  
  METHODS
  Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.
  
  
  RESULTS
  The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.
  
  
  CONCLUSIONS
  Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Angel C Y
authors.initials: AC
authors.lastname: Mak
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Ling Fung
authors.initials: LF
authors.lastname: Tang
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California.
authors.forename: Jinny S
authors.initials: JS
authors.lastname: Wong
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Rahul C
authors.initials: RC
authors.lastname: Deo
authors.affiliation: College of Osteopathic Medicine, Touro University California, Vallejo.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Schwarz
authors.affiliation: College of Osteopathic Medicine, Touro University California, Vallejo.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gugliucci
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Irina
authors.initials: I
authors.lastname: Movsesyan
authors.affiliation: Boston Heart Diagnostics, Framingham, Massachusetts.
authors.forename: Brian Y
authors.initials: BY
authors.lastname: Ishida
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Annie
authors.initials: A
authors.lastname: Poon
authors.affiliation: Darin M. Camarena Health Centers, Madera, California.
authors.forename: Phillip
authors.initials: P
authors.lastname: Kim
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Eveline O
authors.initials: EO
authors.lastname: Stock
authors.affiliation: Boston Heart Diagnostics, Framingham, Massachusetts.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
authors.affiliation: Boston Heart Diagnostics, Framingham, Massachusetts.
authors.forename: Bela F
authors.initials: BF
authors.lastname: Asztalos
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Castellano
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California7Center for Tissue Regeneration, Repair, and Restoration, VA Palo Alto Health Care System, Palo Alto, California.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Department of Ophthalmology, University of California, San Francisco.
authors.forename: Jacque L
authors.initials: JL
authors.lastname: Duncan
authors.affiliation: Memory and Aging Center, University of California, San Francisco.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Malloy
mesh_terms: D000328:Adult; D001054:Apolipoproteins A / Q000097:blood; D001056:Apolipoproteins C / Q000097:blood; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics*; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging; D005080:Exercise Test; D059472:Exome; D016368:Frameshift Mutation; D005838:Genotype; D053442:High-Density Lipoproteins, Pre-beta / Q000097:blood; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D008049:Lipase / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010641:Phenotype; D012160:Retina; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D012871:Skin Diseases / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D014463:Ultrasonography; D014973:Xanthomatosis / Q000235:genetics
chemical_list: D001054:Apolipoproteins A; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D053442:High-Density Lipoproteins, Pre-beta; D008049:Lipase; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014280:Triglycerides; C000715087:ABCC2 protein, human; C504173:LIPC protein, human
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