Hypercholesterolemia induced by spontaneous oligogenic mutations in rhesus macaques (Macaca mulatta)

BACKGROUND A rhesus macaque with the fourth highest plasma cholesterol (CH) levels of 501 breeding macaques was identified 22 years ago. Seven offspring with gene mutations causing hypercholesterolemia were obtained. METHODS Activity of low-density lipoprotein receptor (LDLR), plasma CH levels and mRNA expression levels of LDLR were measured after administration of 0.1% (0.27 mg/kcal) or 0.3% CH. RESULTS Activity of p. (Cys82Tyr) of LDLR was 71% and 42% in the heterozygotes and a homozygote, respectively. The mRNA expression level of LDLR in the p. (Val241Ile) of membrane-bound transcription factor protease, site 2 (MBTPS2, S2P protein) was 0.83 times lower than normal levels. LDLR mRNA levels were increased for up to 4 weeks by administration of 0.3% CH before suddenly decreasing to 80% of the baseline levels after 6 weeks. CONCLUSION Oligogenic mutations of p. (Cys82Tyr) in LDLR and p. (Val241Ile) in MBTPS2 (S2P) caused hypercholesterolemia exceeding cardiovascular risk levels under a 0.1% CH diet.

[1]  E. Knapik,et al.  Metabolic co-essentiality mapping identifies c12orf49 as a regulator of SREBP processing and cholesterol metabolism , 2020, Nature metabolism.

[2]  Marcel Mettlen,et al.  Regulation of Clathrin-Mediated Endocytosis. , 2018, Annual review of biochemistry.

[3]  J. Goldstein,et al.  Retrospective on Cholesterol Homeostasis: The Central Role of Scap. , 2018, Annual review of biochemistry.

[4]  Yiguo Wang,et al.  CRTC2 modulates hepatic SREBP1c cleavage by controlling Insig2a expression during fasting , 2018, Protein & Cell.

[5]  N. Sirisena,et al.  Genetic determinants of inherited susceptibility to hypercholesterolemia – a comprehensive literature review , 2017, Lipids in Health and Disease.

[6]  Robert A. Hegele,et al.  Genetics of Lipid and Lipoprotein Disorders and Traits , 2016, Current Genetic Medicine Reports.

[7]  T. Wieland,et al.  Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction , 2015, European Journal of Human Genetics.

[8]  S. Virani,et al.  Genetics of Familial Hypercholesterolemia , 2015, Current Atherosclerosis Reports.

[9]  S. Itoh,et al.  [Disease animal models for drug research and development]. , 2014, Nihon yakurigaku zasshi. Folia pharmacologica Japonica.

[10]  S. Humphries,et al.  Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations , 2014, Journal of Medical Genetics.

[11]  L. Kroos,et al.  Biochemical and structural insights into intramembrane metalloprotease mechanisms. , 2013, Biochimica et biophysica acta.

[12]  Tanya M. Teslovich,et al.  Discovery and refinement of loci associated with lipid levels , 2013, Nature Genetics.

[13]  Harvey T. McMahon,et al.  Molecular mechanism and physiological functions of clathrin-mediated endocytosis , 2011, Nature Reviews Molecular Cell Biology.

[14]  Donald W. Bowden,et al.  Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project , 2011, PLoS genetics.

[15]  Inês Barroso,et al.  Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[16]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[17]  P. Ridker,et al.  Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis , 2009, PLoS genetics.

[18]  L. Masana,et al.  Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention , 2009, Vascular health and risk management.

[19]  R. Collins,et al.  Common variants at 30 loci contribute to polygenic dyslipidemia , 2009, Nature Genetics.

[20]  Christian Gieger,et al.  Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts , 2009, Nature Genetics.

[21]  C. Hoggart,et al.  Genome-wide association analysis of metabolic traits in a birth cohort from a founder population , 2008, Nature Genetics.

[22]  M. Rieder,et al.  Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication , 2008, Circulation. Cardiovascular genetics.

[23]  I. Holme,et al.  Relationships between lipoprotein components and risk of myocardial infarction: age, gender and short versus longer follow‐up periods in the Apolipoprotein MOrtality RISk study (AMORIS) , 2008, Journal of internal medicine.

[24]  D. Strachan,et al.  LDL-cholesterol concentrations: a genome-wide association study , 2008, The Lancet.

[25]  R. Collins,et al.  Newly identified loci that influence lipid concentrations and risk of coronary artery disease , 2008, Nature Genetics.

[26]  Dolores Corella,et al.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans , 2008, Nature Genetics.

[27]  Mario Falchi,et al.  Genome-wide Association Study Identifies Genes for Biomarkers of Cardiovascular Disease: Serum Urate and Dyslipidemia , 2022 .

[28]  Nieng Yan,et al.  Structure of a Site-2 Protease Family Intramembrane Metalloprotease , 2007, Science.

[29]  O. Takenaka,et al.  Plasma cholesterol levels in free-ranging macaques compared with captive macaques and humans , 2000, Primates.

[30]  G. Walldius,et al.  The apoB/apoA‐I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid‐lowering therapy – a review of the evidence , 2006, Journal of internal medicine.

[31]  P. Tontonoz,et al.  Liver X receptors as integrators of metabolic and inflammatory signaling. , 2006, The Journal of clinical investigation.

[32]  Joseph L. Goldstein,et al.  Protein Sensors for Membrane Sterols , 2006, Cell.

[33]  N. Grishin,et al.  Site‐2 protease regulated intramembrane proteolysis: Sequence homologs suggest an ancient signaling cascade , 2006, Protein science : a publication of the Protein Society.

[34]  Hyesung Jeon,et al.  Structure and physiologic function of the low-density lipoprotein receptor. , 2005, Annual review of biochemistry.

[35]  J. Weissenbach,et al.  Mutations in PCSK9 cause autosomal dominant hypercholesterolemia , 2003, Nature Genetics.

[36]  J. Goldstein,et al.  Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Joseph L. Goldstein,et al.  Structure of the LDL Receptor Extracellular Domain at Endosomal pH , 2002, Science.

[38]  R. Aebersold,et al.  Crucial Step in Cholesterol Homeostasis Sterols Promote Binding of SCAP to INSIG-1, a Membrane Protein that Facilitates Retention of SREBPs in ER , 2002, Cell.

[39]  Joseph L Goldstein,et al.  SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. , 2002, The Journal of clinical investigation.

[40]  Jonathan C. Cohen,et al.  Autosomal Recessive Hypercholesterolemia Caused by Mutations in a Putative LDL Receptor Adaptor Protein , 2001, Science.

[41]  M. S. Brown,et al.  Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by site-2 protease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Goldstein,et al.  Membrane Topology of S2P, a Protein Required for Intramembranous Cleavage of Sterol Regulatory Element-binding Proteins* , 1999, The Journal of Biological Chemistry.

[43]  K. Terao,et al.  Comparison of Four Lymphocyte Isolation Methods and Two Hemolysis Methods for Immuno Flow Cytometric Analysis of Peripheral Lymphocyte Subsets in Rhesus Monkeys (Macaca mulatta) , 1999 .

[44]  P. Espenshade,et al.  Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. , 1998, Molecular cell.

[45]  M. T. Hasan,et al.  Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. , 1997, Molecular cell.

[46]  J. Goldstein,et al.  The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor , 1997, Cell.

[47]  P. Kroon,et al.  Expression and disulfide‐bond connectivity of the second ligand‐binding repeat of the human LDL receptor , 1995, FEBS letters.

[48]  X. Hua,et al.  SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis , 1994, Cell.

[49]  Z. F. Stephan,et al.  Rapid fluorometric assay of LDL receptor activity by DiI-labeled LDL. , 1993, Journal of lipid research.

[50]  L. Neven,et al.  Familial hypercholesterolemia in a rhesus monkey pedigree: molecular basis of low density lipoprotein receptor deficiency. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[51]  R. Krauss,et al.  Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Brown,et al.  A receptor-mediated pathway for cholesterol homeostasis. , 1986, Science.