ABCC2 p.Asn801Ile
| Predicted by SNAP2: | A: N (72%), C: N (66%), D: N (97%), E: N (97%), F: D (53%), G: N (87%), H: N (87%), I: D (53%), K: N (66%), L: D (53%), M: N (57%), P: D (59%), Q: N (82%), R: N (57%), S: N (93%), T: N (82%), V: N (53%), W: D (66%), Y: D (53%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: D, P: N, Q: N, R: N, S: N, T: N, V: D, W: D, Y: D, |
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[hide] Effects of the absence of apolipoprotein e on lipo... JAMA Neurol. 2014 Oct;71(10):1228-36. doi: 10.1001/jamaneurol.2014.2011. Mak AC, Pullinger CR, Tang LF, Wong JS, Deo RC, Schwarz JM, Gugliucci A, Movsesyan I, Ishida BY, Chu C, Poon A, Kim P, Stock EO, Schaefer EJ, Asztalos BF, Castellano JM, Wyss-Coray T, Duncan JL, Miller BL, Kane JP, Kwok PY, Malloy MJ
Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function.
JAMA Neurol. 2014 Oct;71(10):1228-36. doi: 10.1001/jamaneurol.2014.2011., [PMID:25111166]
Abstract [show]
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 beta-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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No. Sentence Comment
202 or Chromosome Positiona SIFT Score Allele Frequencyb ABCC2 nsSNV c.T2009C p.I670T Homozygous rs17222632 0 0.0092 APOE fs del c.291delG p.E97fs Homozygous chr19: 45411844 NA NA BUD13 nsSNV c.C1223T p.P408L Heterozygous rs61730763 0.03 0.04 FUT2 fs del c.811delC p.P271fs Heterozygous rs1799761 NA NA LIPC nsSNV c.G409A p.G137R Heterozygous rs199787635 0 0 LRP2 nsSNV c.T1817C p.V606A Heterozygous rs116332504 0 0.03 MCEE nsSNV c.G428A p.R143H Heterozygous rs115175255 0 0.05 PCCA nsSNV c.G925A p.V309M Heterozygous chr13: 100925538 0 NA PLB1 nsSNV c.A2402T p.N801I Heterozygous rs115240682 0.01 0.04 Abbreviations: fs del, frameshift deletion; NA, not applicable; nsSNV, nonsynonymous single-nucleotide variant; SIFT, Sorting Intolerant From Tolerant.
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ABCC2 p.Asn801Ile 25111166:202:558
status: NEW