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Original Investigation |

Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function

Angel C. Y. Mak, PhD1; Clive R. Pullinger, PhD1; Ling Fung Tang, PhD1; Jinny S. Wong, BS2; Rahul C. Deo, MD, PhD1; Jean-Marc Schwarz, PhD3; Alejandro Gugliucci, MD, PhD3; Irina Movsesyan, BS1; Brian Y. Ishida, PhD4; Catherine Chu, BS1; Annie Poon, BS1; Phillip Kim, MD5; Eveline O. Stock, MD1; Ernst J. Schaefer, MD4; Bela F. Asztalos, PhD4; Joseph M. Castellano, PhD6; Tony Wyss-Coray, PhD6,7; Jacque L. Duncan, MD8; Bruce L. Miller, MD9; John P. Kane, MD, PhD1; Pui-Yan Kwok, MD, PhD1; Mary J. Malloy, MD1
[+] Author Affiliations
1Cardiovascular Research Institute, University of California, San Francisco
2Gladstone Institute of Cardiovascular Disease, San Francisco, California
3College of Osteopathic Medicine, Touro University California, Vallejo
4Boston Heart Diagnostics, Framingham, Massachusetts
5Darin M. Camarena Health Centers, Madera, California
6Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California
7Center for Tissue Regeneration, Repair, and Restoration, VA Palo Alto Health Care System, Palo Alto, California
8Department of Ophthalmology, University of California, San Francisco
9Memory and Aging Center, University of California, San Francisco
JAMA Neurol. 2014;71(10):1228-1236. doi:10.1001/jamaneurol.2014.2011.
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Importance  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).

Objectives  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.

Design, Setting, and Participants  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.

Main Outcome Measures  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 and Relevance  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.

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Figure 1.
Xanthomas of a Patient With Homozygous Apolipoprotein E Deficiency

Palmar crease and morbilliform xanthomas (A) and tuberous xanthomas on the hands (B), elbow (C), and ear (D).

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Figure 2.
Sodium Dodecyl Sulfate–Polyacrylamide Gel Electrophoresis Immunoblots

The abnormal composition of apolipoproteins (apo) in the lipoprotein fractions from the patient (P) is compared with the compositions of his mother (M) and a normolipidemic control participant (C). Equal amounts (20 µg) of total protein were run in each lane. Six antibodies were used against the following: apoB-100, apoA-IV, apoE, apoA-I, apoC-IV, and apoC-III. IDL indicates intermediate-density lipoprotein; LDL, low-density lipoprotein; and VLDL, very low-density lipoprotein.

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Figure 3.
Quantitative Scans of Lipoprint Polyacrylamide Gels

High-density lipoprotein (HDL) subfractions from the patient are compared with 5 representative control samples, measured as the scanned density of Sudan black–stained lipids. There is an abnormal HDL size distribution compared with control samples, with the patient’s HDL having a much higher proportion of small particles (fractions 8, 9, and 10). There is some increase in medium-sized particles (fractions 4, 5, 6, and 7). There is a correspondingly lower percentage in the largest particles (fractions 1, 2, and 3). LDL indicates low-density lipoprotein; VLDL, very low-density lipoprotein.

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Figure 4.
Electron Photomicrographs of Fasting Lipoprotein Fractions Visualized by Negative Staining

Very low-density lipoprotein fractions from a control participant (A) and the patient (B) are similar and contain spherical particles of 15 to 70 nm in diameter. The intermediate-density lipoprotein fraction from a control participant shows mainly round particles of 15 to 35 nm in diameter (C); intermediate-density lipoprotein from the patient appears similar but also has lamellar particles with electron-opaque cores attached to electron-lucent zones (arrowheads) (D). The low-density lipoprotein fraction from a control participant displays smaller, largely spherical particles of 15 to 25 nm in diameter (E); in contrast, low-density lipoprotein from the patient has a much more heterogeneous size distribution from 10 to 40 nm in diameter, again with the presence of lamellar particles (arrowheads) (F). Scale bar = 200 nm.

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