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John R. Burnett - One of the best experts on this subject based on the ideXlab platform.
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Novel APOB missense variants, A224T and V925L, in a black South African woman with marked hypocholesterolemia.
Journal of Clinical Lipidology, 2016Co-Authors: Sharon A. Miller, Amanda J. Hooper, George A. Mantiri, A. David Marais, Donald M. Tanyanyiwa, C. James Mcknight, John R. BurnettAbstract:Background One genetic cause of markedly low plasma concentrations of apolipoprotein (apo) B and low density lipoprotein (LDL)-cholesterol is Familial Hypobetalipoproteinemia. Objective We aimed to determine the molecular basis for the marked hypocholesterolemia consistent with heterozygous Familial Hypobetalipoproteinemia in a black female subject of Xhosa lineage. Methods Coding regions of APOB , MTTP , PCSK9, ANGPTL3 , SAR1B and APOC3 were sequenced, and APOE was genotyped. COS-7 cells were transfected with plasmids containing apoB variants. Western blotting was used to detect cellular and secreted apoB, and co-immunoprecipitation performed to assess binding with the microsomal triglyceride transfer protein (MTP). Results Sequence analysis of the APOB gene revealed her to be heterozygous for two novel variants, c.751G>A (A224T) and c.2854G>C (V925L). She was also homozygous for the APOE e 2 allele, and did not carry a PCSK9 loss-of-function mutation. Although Ala 224 is within the postulated MTP binding region in apoB, it is not conserved among mammalian species. Subsequent genotyping showed that Ala224Thr is found in a southern African population (n=654) with an allele frequency of 1.15% and is not associated with plasma lipid levels. Val 925 , like Ala 224 , is within the N-terminal 1000 amino acids required for lipoprotein assembly, but was not found in the population screen. However, in vitro studies showed that apoB V925L did not affect apoB48 production or secretion nor have a deleterious effect on MTP interaction with apoB. Conclusion Taken together, this suggests that the hypocholesterolemia in our case may be a result of being homozygous for APOE e 2 with a low baseline cholesterol.
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Vitamin E and oxidative stress in abetalipoproteinemia and Familial Hypobetalipoproteinemia.
Free Radical Biology and Medicine, 2015Co-Authors: John R. Burnett, Amanda J. HooperAbstract:Abetalipoproteinemia (ABL) and Familial Hypobetalipoproteinemia (FHBL) are genetic diseases characterized by low density lipoprotein deficiency. ABL presents early in life with the gastroenterological manifestations of fat malabsorption, steatorrhea, and failure to thrive, and later in life, with progressive ophthalmopathy and neuropathy as a result of deficiency of the fat-soluble vitamins A and E. Heterozygous FHBL subjects are usually asymptomatic, but may develop fatty liver disease. In homozygous (compound heterozygous) FHBL, the clinical and biochemical features are indistinguishable from those of ABL and treatment recommendations are the same: dietary fat restriction to prevent steatorrhea, and long-term high-dose vitamin E and A supplementation to prevent or at least slow the progression of neuromuscular and retinal degenerative disease. Despite their low plasma vitamin E levels, individuals with heterozygous FHBL do not require vitamin E supplementation. There are conflicting reports on whether increased oxidative stress is seen in ABL; these differences may relate to the small size of patient groups as well as differences in patient age and dose of vitamin E supplementation, or the contribution from dietary sources of vitamin E. High density lipoproteins in ABL appear to be severely oxidized yet able to inhibit platelet aggregation by binding to scavenger receptor B1. We review the role of vitamin E and oxidative stress in ABL and FHBL.
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Liver Dysfunction and Steatosis in Familial
2014Co-Authors: Frank M. Van Bockxmeer, John R. BurnettAbstract:A 32-year-old man presented with increased serum alanine aminotransferase activity and iron concentra-tion and transferrin saturation suggestive of hepatic dysfunction and iron overload. In addition, he had unusually low plasma concentrations of LDL choles-terol and apolipoprotein (apo) B. Hepatic ultrasonogra-phy was consistent with fatty liver. On liver biopsy, marked steatosis and moderate to marked iron deposi-tion were observed. The patient was found to carry the HFE C282Y and H63D mutations, which are associated with hereditary hemochromatosis, and the 1-antitryp-sin PiZ variant. An immunoblot of plasma for apoB showed the presence of a truncated apoB species, indic-ative of Familial Hypobetalipoproteinemia. DNA se-quence analysis revealed that the patient was heterozy
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abstract 236 lipoprotein metabolism in apob l343v Familial Hypobetalipoproteinemia
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Amanda J. Hooper, K. Robertson, Klaus G. Parhofer, Frank M. Van Bockxmeer, Liesl V. Heeks, Danie Champain, Hugh P R Barrett, John R. BurnettAbstract:Familial Hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of LDL-cholesterol and apolipoprotein (apo) B. We examined the effect of heterozygous APOB L343V FHBL on fasting and postprandial lipoprotein metabolism. VLDL, IDL-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. VLDL-apoB concentrations in FHBL subjects (n=2) were reduced by more than 75% compared to healthy, normolipidemic control subjects (P<0.01). VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects (P=0.07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. To assess postprandial lipoprotein metabolism, a standardized oral fat load was given after a 12 h fast to heterozygous APOB L343V FHBL subjects (n=3) and normolipidemic controls. The postprandial incremental area under the curve (0-10 h) in FHBL subje...
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postprandial lipoprotein metabolism in Familial Hypobetalipoproteinemia
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Amanda J. Hooper, K. Robertson, Klaus G. Parhofer, Frank M. Van Bockxmeer, John R. Burnett, Hugh P R BarrettAbstract:Objective: Familial Hypobetalipoproteinemia (FHBL) is an autosomal codominantly inherited disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein-cholesterol and apolipoprotein (apo) B. We examined the effect of truncated apoB variants (
Maurizio Averna - One of the best experts on this subject based on the ideXlab platform.
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Association between Familial Hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol–diabetes connection? A systematic review of literature
Acta Diabetologica, 2017Co-Authors: Davide Noto, Patrizia Tarugi, Angelo B. Cefalù, Carlo M. Barbagallo, Marcello Arca, Maurizio AvernaAbstract:Statin therapy is beneficial in reducing LDL cholesterol (LDL-C) levels and cardiovascular events, but it is associated with the risk of incident diabetes mellitus (DM). Familial hypercholesterolemia (FH) is characterized by genetically determined high levels of plasma LDL-C and a low prevalence of DM. LDL-C levels seem then inversely correlated with prevalence of DM. Familial Hypobetalipoproteinemia (FHBL) represents the genetic mirror of FH in terms of LDL-C levels, very low in subjects carrying mutations of APOB , PCSK9 (FHBL1) or ANGPTL3 (FHBL2). This review explores the hypothesis that FHBL might represent also the genetic mirror of FH in terms of prevalence of DM and that it is expected to be increased in FHBL in comparison with the general population. A systematic review of published literature on FHBL was made by searching PubMed (1980–2016) for articles presenting clinical data on FHBL probands and relatives. The standardized prevalence rates of DM in FHBL1 were similar to those of the reference population, with a prevalence rate of 8.2 and 9.2%, respectively, while FHBL2 showed a 4.9% prevalence of DM. In conclusion, low LDL-C levels of FHBL do not seem connected to DM as it happens in subjects undergoing statin therapy and the diabetogenic effect of statins has to be explained by mechanisms that do not rely exclusively on the reduced levels of LDL-C. The review also summarizes the published data on the effects of FHBL on insulin sensitivity and the relationships between FH, statin therapy, FHBL1 and intracellular cholesterol metabolism, evaluating possible diabetogenic pathways.
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Association between Familial Hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol-diabetes connection? A systematic review of literature.
Acta Diabetologica, 2016Co-Authors: Davide Noto, Patrizia Tarugi, Angelo B. Cefalù, Carlo M. Barbagallo, Marcello Arca, Maurizio AvernaAbstract:Statin therapy is beneficial in reducing LDL cholesterol (LDL-C) levels and cardiovascular events, but it is associated with the risk of incident diabetes mellitus (DM). Familial hypercholesterolemia (FH) is characterized by genetically determined high levels of plasma LDL-C and a low prevalence of DM. LDL-C levels seem then inversely correlated with prevalence of DM. Familial Hypobetalipoproteinemia (FHBL) represents the genetic mirror of FH in terms of LDL-C levels, very low in subjects carrying mutations of APOB, PCSK9 (FHBL1) or ANGPTL3 (FHBL2). This review explores the hypothesis that FHBL might represent also the genetic mirror of FH in terms of prevalence of DM and that it is expected to be increased in FHBL in comparison with the general population. A systematic review of published literature on FHBL was made by searching PubMed (1980–2016) for articles presenting clinical data on FHBL probands and relatives. The standardized prevalence rates of DM in FHBL1 were similar to those of the reference population, with a prevalence rate of 8.2 and 9.2%, respectively, while FHBL2 showed a 4.9% prevalence of DM. In conclusion, low LDL-C levels of FHBL do not seem connected to DM as it happens in subjects undergoing statin therapy and the diabetogenic effect of statins has to be explained by mechanisms that do not rely exclusively on the reduced levels of LDL-C. The review also summarizes the published data on the effects of FHBL on insulin sensitivity and the relationships between FH, statin therapy, FHBL1 and intracellular cholesterol metabolism, evaluating possible diabetogenic pathways.
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Characterization of a mutant form of human apolipoprotein B (Thr26_Tyr27del) associated with Familial Hypobetalipoproteinemia.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2016Co-Authors: Lucia Magnolo, Zemin Yao, Maurizio Averna, Davide Noto, Angelo B. Cefalù, Sebastiano Calandra, Patrizia TarugiAbstract:We have previously identified a deletion mutant of human apoB [apoB (Thr26_Tyr27del)] in a subject with primary Hypobetalipoproteinemia. The present study determined the effect of Thr26_Tyr27del mutation on apoB secretion using transfected McA-RH7777 cells. Transient or stable transfection of apoB-48 containing the Thr26_Tyr27del mutation showed drastically reduced secretion of the mutant as compared to wild-type apoB-48. No lipoproteins containing the mutant apoB-48 were secreted into the medium. Incubation of transfected cells in a lipid-rich medium in the presence of cycloheximide showed rapid turnover of cell-associated mutant apoB-48 as compared to that of wild-type apoB-48. Immunofluorescence experiments showed that the mutant apoB-48 was mostly localized in the endoplasmic reticulum. Treatment with the proteasomal inhibitor MG132 markedly attenuated the turnover of cell-associated mutant apoB-48, whereas treatment with inhibitors of autophagosomal/lysosomal function (e.g. 3-MA or ammonium chloride) had no effect. Taken together, these results indicated that the defective secretion of the Thr26_Tyr27del mutant was associated with increased intracellular degradation of apoB through the proteasome-dependent pathway.
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and Chemistry,
2015Co-Authors: G. Schonfeld, Maurizio Averna, Tariq Tanoli, Bruce W. Patterson, Dmitriy A. Yablonskiy, Nizar EliasAbstract:Fatty liver in Familial Hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosi
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A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Tommaso Fasano, Enza Di Leo, Davide Noto, Angelo B. Cefalù, Vincenza Valenti, Daniela Pollaccia, L. Bocchi, Renato Bonardi, Ornella Guardamagna, Maurizio AvernaAbstract:Objectives— The PCSK9 gene, encoding a pro-protein convertase involved in posttranslational degradation of low-density lipoprotein receptor, has emerged as a key regulator of plasma low-density lipoprotein cholesterol. In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. The aim of this study was to assess whether loss of function mutations of PCSK9 were a cause of Familial Hypobetalipoproteinemia and a determinant of low-plasma low-density lipoprotein cholesterol in whites. Methods and Results— We sequenced PCSK9 gene in 18 Familial Hypobetalipoproteinemia subjects and in 102 hypocholesterolemic blood donors who were negative for APOB gene mutations known to cause Familial Hypobetalipoproteinemia. The PCSK9 gene variants found in these 2 groups were screened in 42 subjects in the lowest ( 95th) percentile, and 100 with the average plasma cholesterol ...
G. Schonfeld - One of the best experts on this subject based on the ideXlab platform.
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and Chemistry,
2015Co-Authors: G. Schonfeld, Maurizio Averna, Tariq Tanoli, Bruce W. Patterson, Dmitriy A. Yablonskiy, Nizar EliasAbstract:Fatty liver in Familial Hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosi
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Familial Hypobetalipoproteinemia in a hospital survey: genetics, metabolism and non-alcoholic fatty liver disease.
Annals of Hepatology, 2011Co-Authors: Carlos Gutiérrez-cirlos, María Teresa Tusié-luna, G. Schonfeld, Bruce W. Patterson, María Luisa Ordóñez-sánchez, Carlos A. Aguilar-salinasAbstract:Introduction. Familial Hypobetalipoproteinemia (FHBL) is an autosomal dominant disease characterized by abnormally low levels of apolipoprotein-B (apoB) containing lipoproteins. FHBL is caused by APOB, PCSK9 or ANGPTL3 mutations or is associated with loci located in chromosomes 10 and 3p21. However, other genes should be involved. This study describes the kinetic parameters of the apoB containing lipoproteins and sequence abnormalities of the APOB and PCSK9 genes of FHBL patients identified in a large hospital based survey. Material and methods. Cases with primary or secondary causes of Hypobetalipoproteinemia were identified. ApoB kinetics were measured in cases with primary forms in whom truncated forms of apoB were not present in VLDL (n = 4). A primed constant infusion of [ 13 C] leucine was administered, VLDL and LDL apoB production and catabolic rates measured by a multicompartmental model and compared to normolipemic controls. In addition, these subjects had an abdominal ultrasound and direct sequencing was carried out for the PCSK9 and apoB genes. Results. Three individuals had normal apoB production with increased catabolic rate; the remaining had reduced synthetic and catabolic rates. Various polymorphisms, some of them previously unreported (*), in the PCSK9 gene (R46L, A53V, I474V, D480N*, E498K*) and in the apoB gene (N441D*, Y1395C, P2712L, D2285E*, I2286V, T3540S*, T3799M*) were found in the FHBL patients. We found hepatic ultrasound changes of hepatic steatosis in only one of the four probands. Conclusion. FHBL without truncated apoB is a heterogeneous disease from a metabolic and a genetic perspective. Hypobetalipoproteinemia is a risk factor but not an obligate cause of steatosis.
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Familial Hypobetalipoproteinemia genetics and metabolism
Cellular and Molecular Life Sciences, 2005Co-Authors: G. Schonfeld, X. Lin, P. YueAbstract:Familial Hypobetalipoproteinemia (FHBL), an autosomal dominant disorder, is defined as <5th percentile LDL-cholesterol or apolipoprotein (apo) B in the plasma. FHBL subjects are generally heterozygous and asymptomatic. Three genetic forms exist: (i) premature stop codon specifying mutations of APOB; (ii) FHBL linked to a susceptibility locus on the chromosome 3p21; and (iii) FHBL linked neither to APOB nor to the chromosome 3p21. In heterozygous apoB-defective FHBL, the hepatic VLDL export system is defective because apoB 100, the product of the normal allele, is produced at ∼5% of normal rate, and truncated apoB is cleared too rapidly. The reduced capacity for hepatic triglyceride export increases hepatic fat three-fold. Indexes of adiposity and insulin action are similar to controls. ‘Knock-in’ mouse models of apoB truncations resemble human FHBL phenotypes. Liver fat in the chromosome 3p21-linked FHBL is normal. Elucidation of the genetic basis of the non-apoB FHBL could uncover attractive targets for lipid-lowering therapy. (See note added in proof.)
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review Familial Hypobetalipoproteinemia genetics and metabolism
2005Co-Authors: G. Schonfeld, X. Lin, P. YueAbstract:Familial Hypobetalipoproteinemia (FHBL), an autosomal dominant disorder, is defined as <5 th percentile LDL-cholesterol or apolipoprotein (apo) B in the plasma. FHBL subjects are generally heterozygous and asymp- tomatic. Three genetic forms exist: (i) premature stop codon specifying mutations of APOB; (ii) FHBL linked to a susceptibility locus on the chromosome 3p21; and (iii) FHBL linked neither to APOB nor to the chromosome 3p21. In heterozygous apoB-defective FHBL, the hepatic VLDL export system is defective because apoB 100, the
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Familial Hypobetalipoproteinemia a review
Journal of Lipid Research, 2003Co-Authors: G. SchonfeldAbstract:We review the genetics and pathophysiology of Familial Hypobetalipoproteinemia (FHBL), a mildly symptomatic genetically heterogeneous autosomal trait. The minority of human FHBL is caused by truncation-specifying mutations of the APOB gene on chromosome 2. In seven families, linkage to chromosome 2 is absent, linkage is instead to chromosome 3 (3p21). In others, linkage is absent to both APOB and to 3p21. Apolipoprotein B-100 (apoB-100) levels are approximately 25% of normal, instead of the 50% expected based on the presence of one normal allele due to reduced rates of production. The presence of the truncating mutation seems to have a "dominant recessive" effect on apoB-100 secretion. Concentrations of apoB truncations in plasma differ by truncation but average at approximately 10% of normal levels. Lipoproteins bearing truncated forms of apoB are cleared more rapidly than apoB-100 particles. In contrast with apoB-100 particles cleared primarily in liver via the LDL receptor, most apoB truncation particles are cleared in renal proximal tubular cells via megalin. Since apoB defects cause a dysfunctional VLDL-triglyceride transport system, livers accumulate fat. Hepatic synthesis of fatty acids is reduced in compensation. Informational lacunae remain about genes affecting fat accumulation in liver, and the modulation of liver fat in the presence apoB truncation defects.
Patrizia Tarugi - One of the best experts on this subject based on the ideXlab platform.
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In vitro functional characterization of splicing variants of the APOB gene found in Familial Hypobetalipoproteinemia.
Journal of Clinical Lipidology, 2019Co-Authors: Claudio Rabacchi, Enza Di Leo, Stefano Bertolini, Sebastiano Calandra, Maria Luisa Simone, Livia Pisciotta, Davide Bocchi, Antonello Pietrangelo, Sergio D'addato, Patrizia TarugiAbstract:Background Familial Hypobetalipoproteinemia type 1 (FHBL-1) is a codominant disorder characterized by greatly reduced plasma levels of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B. Rare exonic pathogenic variants of APOB gene (nonsense variants, minute deletions/insertions and nonsynonymous variants) have been frequently reported in subjects with FHBL-1. Also, rare intronic variants of APOB located at intron/exon junctions and assumed to affect splicing have been reported. However, the pathogenicity of most of these intronic variants remains to be established. Objective The objective of this study was the in vitro functional characterization of six splicing variants of APOB gene identified in seven putative FHBL-1 heterozygotes. Methods ApoB minigenes harboring each variant were expressed in COS-1 cells and their transcripts were sequenced. Results Four novel variants (c.237+1G>A, c.818+5G>A, c.3000-1G>T, and c.3842+1G>A), predicted in silico to obliterate splice site activity, were found to generate abnormal transcripts. The abnormal transcripts were generated by the activation of cryptic splice sites or exon skipping. All these transcripts harbored a premature termination codon and were predicted to encode truncated apoBs devoid of function. The predicted translation products were: i) p.(Lys41Serfs*2) and p.(Val80Ilefs*10) for c.237+1G>A; ii) p.(Asn274*) for c.818+5G>A; iii) p.(Leu1001Alafs*10) for c.3000-1G>T, and iv) p.(Ser1281Argfs*2) for c.3842+1G>A. Two previously annotated rare variants (c.905-15C>G and c.1618-4G>A) with uncertain effect in silico were found to generate only wild-type transcripts. Conclusions These in vitro minigene expression studies support the assignment of pathogenicity to four novel splice site variants of APOB gene found in FHBL-1.
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Association between Familial Hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol–diabetes connection? A systematic review of literature
Acta Diabetologica, 2017Co-Authors: Davide Noto, Patrizia Tarugi, Angelo B. Cefalù, Carlo M. Barbagallo, Marcello Arca, Maurizio AvernaAbstract:Statin therapy is beneficial in reducing LDL cholesterol (LDL-C) levels and cardiovascular events, but it is associated with the risk of incident diabetes mellitus (DM). Familial hypercholesterolemia (FH) is characterized by genetically determined high levels of plasma LDL-C and a low prevalence of DM. LDL-C levels seem then inversely correlated with prevalence of DM. Familial Hypobetalipoproteinemia (FHBL) represents the genetic mirror of FH in terms of LDL-C levels, very low in subjects carrying mutations of APOB , PCSK9 (FHBL1) or ANGPTL3 (FHBL2). This review explores the hypothesis that FHBL might represent also the genetic mirror of FH in terms of prevalence of DM and that it is expected to be increased in FHBL in comparison with the general population. A systematic review of published literature on FHBL was made by searching PubMed (1980–2016) for articles presenting clinical data on FHBL probands and relatives. The standardized prevalence rates of DM in FHBL1 were similar to those of the reference population, with a prevalence rate of 8.2 and 9.2%, respectively, while FHBL2 showed a 4.9% prevalence of DM. In conclusion, low LDL-C levels of FHBL do not seem connected to DM as it happens in subjects undergoing statin therapy and the diabetogenic effect of statins has to be explained by mechanisms that do not rely exclusively on the reduced levels of LDL-C. The review also summarizes the published data on the effects of FHBL on insulin sensitivity and the relationships between FH, statin therapy, FHBL1 and intracellular cholesterol metabolism, evaluating possible diabetogenic pathways.
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Association between Familial Hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol-diabetes connection? A systematic review of literature.
Acta Diabetologica, 2016Co-Authors: Davide Noto, Patrizia Tarugi, Angelo B. Cefalù, Carlo M. Barbagallo, Marcello Arca, Maurizio AvernaAbstract:Statin therapy is beneficial in reducing LDL cholesterol (LDL-C) levels and cardiovascular events, but it is associated with the risk of incident diabetes mellitus (DM). Familial hypercholesterolemia (FH) is characterized by genetically determined high levels of plasma LDL-C and a low prevalence of DM. LDL-C levels seem then inversely correlated with prevalence of DM. Familial Hypobetalipoproteinemia (FHBL) represents the genetic mirror of FH in terms of LDL-C levels, very low in subjects carrying mutations of APOB, PCSK9 (FHBL1) or ANGPTL3 (FHBL2). This review explores the hypothesis that FHBL might represent also the genetic mirror of FH in terms of prevalence of DM and that it is expected to be increased in FHBL in comparison with the general population. A systematic review of published literature on FHBL was made by searching PubMed (1980–2016) for articles presenting clinical data on FHBL probands and relatives. The standardized prevalence rates of DM in FHBL1 were similar to those of the reference population, with a prevalence rate of 8.2 and 9.2%, respectively, while FHBL2 showed a 4.9% prevalence of DM. In conclusion, low LDL-C levels of FHBL do not seem connected to DM as it happens in subjects undergoing statin therapy and the diabetogenic effect of statins has to be explained by mechanisms that do not rely exclusively on the reduced levels of LDL-C. The review also summarizes the published data on the effects of FHBL on insulin sensitivity and the relationships between FH, statin therapy, FHBL1 and intracellular cholesterol metabolism, evaluating possible diabetogenic pathways.
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Homozygous Familial Hypobetalipoproteinemia: A Turkish case carrying a missense mutation in apolipoprotein B.
Clinica Chimica Acta, 2016Co-Authors: Berna Seker Yilmaz, Enza Di Leo, Lucia Magnolo, Neslihan Önenli Mungan, Lucia Artuso, Isabella Bernardis, Gokhan Tumgor, Deniz Kör, Patrizia TarugiAbstract:The autosomal co-dominant disorder Familial Hypobetalipoproteinemia (FHBL) may be due to mutations in the APOB gene encoding apolipoprotein B (apoB), the main constituent peptide of chylomicrons, very low and low density lipoproteins. We describe an 11month-old child with failure to thrive, intestinal lipid malabsorption, hepatic steatosis and severe Hypobetalipoproteinemia, suggesting the diagnosis of homozygous FHBL, abetalipoproteinemia (ABL) or chylomicron retention disease (CMRD). The analysis of candidate genes showed that patient was homozygous for a variant (c.1594 C>T) in the APOB gene causing arginine to tryptophan conversion at position 505 of mature apoB (Arg505Trp). No mutations were found in a panel of other potential candidate genes for Hypobetalipoproteinemia. In vitro studies showed a reduced secretion of mutant apoB-48 with respect to the wild-type apoB-48 in transfected McA-RH7777 cells. The Arg505Trp substitution is located in the βα1 domain of apoB involved in the lipidation of apoB mediated by microsomal triglyceride transfer protein (MTP), the first step in VLDL and chylomicron formation. The patient's condition improved in response to a low fat diet supplemented with fat-soluble vitamins. Homozygosity for a rare missense mutation in the βα1 domain of apoB may be the cause of both severe Hypobetalipoproteinemia and intestinal lipid malabsorption.
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Characterization of a mutant form of human apolipoprotein B (Thr26_Tyr27del) associated with Familial Hypobetalipoproteinemia.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2016Co-Authors: Lucia Magnolo, Zemin Yao, Maurizio Averna, Davide Noto, Angelo B. Cefalù, Sebastiano Calandra, Patrizia TarugiAbstract:We have previously identified a deletion mutant of human apoB [apoB (Thr26_Tyr27del)] in a subject with primary Hypobetalipoproteinemia. The present study determined the effect of Thr26_Tyr27del mutation on apoB secretion using transfected McA-RH7777 cells. Transient or stable transfection of apoB-48 containing the Thr26_Tyr27del mutation showed drastically reduced secretion of the mutant as compared to wild-type apoB-48. No lipoproteins containing the mutant apoB-48 were secreted into the medium. Incubation of transfected cells in a lipid-rich medium in the presence of cycloheximide showed rapid turnover of cell-associated mutant apoB-48 as compared to that of wild-type apoB-48. Immunofluorescence experiments showed that the mutant apoB-48 was mostly localized in the endoplasmic reticulum. Treatment with the proteasomal inhibitor MG132 markedly attenuated the turnover of cell-associated mutant apoB-48, whereas treatment with inhibitors of autophagosomal/lysosomal function (e.g. 3-MA or ammonium chloride) had no effect. Taken together, these results indicated that the defective secretion of the Thr26_Tyr27del mutant was associated with increased intracellular degradation of apoB through the proteasome-dependent pathway.
Bertrand Cariou - One of the best experts on this subject based on the ideXlab platform.
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Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia
Disease Models & Mechanisms, 2015Co-Authors: Karim Si-tayeb, Salam Idriss, Benoite Champon, Amandine Caillaud, Matthieu Pichelin, Lucie Arnaud, Patricia Lemarchand, Céric Le May, Kazem Zibara, Bertrand CariouAbstract:Proprotein convertase subtilisin kexin type 9 (PCSK9) is a critical modulator of cholesterol homeostasis. Whereas PCSK9 gain-of-function (GOF) mutations are associated with autosomal dominant hypercholesterolemia (ADH) and premature atherosclerosis, PCSK9 loss-of-function (LOF) mutations have a cardio-protective effect and in some cases can lead to Familial Hypobetalipoproteinemia (FHBL). However, limitations of the currently available cellular models preclude deciphering the consequences of PCSK9 mutation further. We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL. To achieve our goal, urine-sample-derived somatic cells were reprogrammed into hiPSCs by using episomal vectors. UhiPSC were efficiently differentiated into hepatocyte-like cells (HLCs). Compared to control cells, cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (−38.5%; P=0.038) and had a 71% decrease (P
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pcsk9 dominant negative mutant results in increased ldl catabolic rate and Familial Hypobetalipoproteinemia
Arteriosclerosis Thrombosis and Vascular Biology, 2009Co-Authors: Bertrand Cariou, Khadija Ouguerram, Yassine Zair, Raphael Guerois, Cedric Langhi, Sanae Kourimate, Isabelle Benoit, Cedric Le May, Constance Gayet, Khaldia BelabbasAbstract:Objective— Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central player in the regulation of cholesterol homeostasis, increasing the low-density lipoprotein (LDL) receptor degradation. Our study aimed at exploring the pathogenic consequences in vivo and in vitro of a PCSK9 prodomain mutation found in a family with Hypobetalipoproteinemia (FHBL). Methods and Results— A white 49-year-old diabetic man had profound FBHL (LDLC: 16 mg/dL) whereas his daughter and sister displayed a milder phenotype (LDLC 44 mg/dL and 57 mg/dL, respectively), all otherwise healthy with a normal liver function. A monoallelic PCSK9 double-mutant R104C/V114A cosegregated with FBHL, with no mutation found at other FHBL-causing loci. A dose-effect was also found in FBHL relatives for plasma APOB and PCSK9 (very-low to undetectable in proband, ≈50% decreased in sister and daughter) and LDL catabolic rate (256% and 88% increased in proband and daughter). Transient transfection in hepatocytes showed severely impaired processing and secretion of the double mutant which acted as a dominant negative over secretion of wild-type PCSK9. Conclusion— These results show that heterozygous PCSK9 missense mutations may associate with profound Hypobetalipoproteinemia and constitute the first direct evidence in human that decrease of plasma LDLC concentrations associated to PCSK9 LOF mutations are attributable to an increased clearance rate of LDL.