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John R. Burnett - One of the best experts on this subject based on the ideXlab platform.
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Lipoprotein metabolism in an apoB-80 familial Hypobetalipoproteinemia heterozygote
Clinical Biochemistry, 2016Co-Authors: Amanda J. Hooper, K. Robertson, P. Hugh R. Barrett, Klaus G. Parhofer, Frank M. Van Bockxmeer, Danie Champain, Jianmin Hua, Swithin Song, John R. BurnettAbstract:Objective: Familial Hypobetalipoproteinemia (FHBL) is characterized by mutations in APOB, the majority of these causing protein truncations, and low plasma levels of apolipoprotein (apo) B. The Hypobetalipoproteinemia may be due to enhanced clearance and possibly reduced production of apoB-containing lipoproteins;the mechanism may depend on the length of the apoB truncation. We studied fasting lipoprotein metabolism in an FHBL subject heterozygous for a mutation causing a truncated apoB, apoB-80. Design and Methods: Very low density lipoprotein (VLDL)-, intermediate density lipoprotein (IDL)-, and low density lipoprotein (LDL)-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. Results: Compared with lean normolipidemic controls the apoB-80 FHBL subject had an elevated VLDL-apoB fractional catabolic rate and lower LDL production. ApoB production rates and IDL- and LDL-apoB fractional catabolic rates were not different. Conclusion: FHBL subjects heterozygous for a mutation truncating apoB to 80% of full-length are able to produce VLDL-apoB normally, but have rapid clearance of these particles, resulting in low levels of circulating apoB. (C) 2016 The Canadian Society of Clinical Chemists. Published by ELSEVIER. All rights reserved.
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Genetic Abetalipoproteinaemia and Hypobetalipoproteinaemia
Dyslipidemias, 2015Co-Authors: Amanda J. Hooper, John R. BurnettAbstract:The monogenic hypocholesterolaemic lipid disorders are classified depending on the lipid biochemical phenotype, gene involved, and mode of inheritance of the condition, together with the severity of the mutation or mutations present. These disorders may or may not be associated with clinical manifestations such as fat malabsorption, growth failure, fat-soluble vitamin deficiency, fatty liver disease, and neuro-ophthalmological dysfunction. We have reviewed the molecular basis, pathogenesis, and clinical aspects of these disorders of apolipoprotein (apo) B production and catabolism, focusing on abetalipoproteinaemia, familial hypobetalipoproteinaemia, and chylomicron retention disease.
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Update on Primary Hypobetalipoproteinemia
Current Atherosclerosis Reports, 2014Co-Authors: Amanda J. Hooper, John R. BurnettAbstract:“Primary Hypobetalipoproteinemia” refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low-density lipoprotein cholesterol and apolipoprotein B in plasma. Abetalipoproteinemia and homozygous familial Hypobetalipoproteinemia, although caused by mutations in different genes, are clinically indistinguishable. A framework for the clinical follow-up and management of these two disorders has been proposed recently, focusing on monitoring of growth in children and preventing complications by providing specialized dietary advice and fat-soluble vitamin therapeutic regimens. Other recent publications on familial combined hypolipidemia suggest that although a reduction of angiopoietin-like 3 activity may improve insulin sensitivity, complete deficiency also reduces serum cholesterol efflux capacity and increases the risk of early vascular atherosclerotic changes, despite low low-density lipoprotein cholesterol levels. Specialist laboratories offer exon-by-exon sequence analysis for the molecular diagnosis of primary Hypobetalipoproteinemia. In the future, massively parallel sequencing of panels of genes involved in dyslipidemia may play a greater role in the diagnosis of these conditions.
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Postprandial lipoprotein metabolism in familial Hypobetalipoproteinemia.
The Journal of Clinical Endocrinology & Metabolism, 2007Co-Authors: Amanda J. Hooper, K. Robertson, P. Hugh R. Barrett, Klaus G. Parhofer, Frank M. Van Bockxmeer, John R. BurnettAbstract: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 (
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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 (
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, G. Schonfeld, Bruce W. Patterson, María Luisa Ordóñez-sánchez, María Teresa Tusié-luna, 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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A targeted apoB38.9 mutation in mice is associated with reduced hepatic cholesterol synthesis and enhanced lipid peroxidation
American Journal of Physiology-gastrointestinal and Liver Physiology, 2006Co-Authors: Xiaobo Lin, Maurizio Averna, Pin Yue, Zhouji Chen, Richard E. Ostlund, Mark A. Watson, G. SchonfeldAbstract:Familial Hypobetalipoproteinemia (FHBL) due to truncation-specifying mutations of apolipoprotein B (apoB), which impair hepatic lipid export in very low-density lipoprotein (VLDL) particles, is ass...
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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
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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.)
Maurizio Averna - 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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Plasma non-cholesterol sterols in primary Hypobetalipoproteinemia.
Atherosclerosis, 2011Co-Authors: Davide Noto, Patrizia Tarugi, Pin Yue, Angelo B. Cefalù, Giacoma Barraco, Francesca Fayer, Mariangela Mina, Gustav Schonfeld, Maurizio AvernaAbstract:Primary Hypobetalipoproteinemia (pHBL) is characterized by plasma cholesterol levels ApoB48, and FHBL harbouring as yet unknown molecular defects. Not linked FHBL kindred are not homogeneous in terms of plasma NCS levels. NCS cannot replace genetic HBL analysis.
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Genetics of familial Hypobetalipoproteinemia
Future Lipidology, 2007Co-Authors: Patrizia Tarugi, Maurizio AvernaAbstract:Primary Hypobetalipoproteinemias include three monogenic disorders: the relatively frequent codominant familial Hypobetalipoproteinemia (FHBL), the rare recessive conditions abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD). Approximately 50% of FHBL patients are carriers of mutations in the APOB gene, mostly causing the formation of truncated forms of ApoB. In some kindred, FHBL is linked to a locus on chromosome 3 (3p21), but the candidate gene is still unknown. Recently, a FHBL-like phenotype was observed in carriers of mutations of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene causing loss-of-function of the encoded protein, a proprotein convertase that regulates LDL-receptor number in the liver. Inactivation of the PCSK9 protein is associated with an increased number of LDL receptors and increased receptor-mediated hepatic uptake of plasma LDL. ABL and CMRD are due to mutations in the microsomal triglyceride transfer protein and Sar1-ADP-ribosylation GTPase 2 genes,...
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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 ...
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A targeted apoB38.9 mutation in mice is associated with reduced hepatic cholesterol synthesis and enhanced lipid peroxidation
American Journal of Physiology-gastrointestinal and Liver Physiology, 2006Co-Authors: Xiaobo Lin, Maurizio Averna, Pin Yue, Zhouji Chen, Richard E. Ostlund, Mark A. Watson, G. SchonfeldAbstract:Familial Hypobetalipoproteinemia (FHBL) due to truncation-specifying mutations of apolipoprotein B (apoB), which impair hepatic lipid export in very low-density lipoprotein (VLDL) particles, is ass...
Amanda J. Hooper - One of the best experts on this subject based on the ideXlab platform.
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Lipoprotein metabolism in an apoB-80 familial Hypobetalipoproteinemia heterozygote
Clinical Biochemistry, 2016Co-Authors: Amanda J. Hooper, K. Robertson, P. Hugh R. Barrett, Klaus G. Parhofer, Frank M. Van Bockxmeer, Danie Champain, Jianmin Hua, Swithin Song, John R. BurnettAbstract:Objective: Familial Hypobetalipoproteinemia (FHBL) is characterized by mutations in APOB, the majority of these causing protein truncations, and low plasma levels of apolipoprotein (apo) B. The Hypobetalipoproteinemia may be due to enhanced clearance and possibly reduced production of apoB-containing lipoproteins;the mechanism may depend on the length of the apoB truncation. We studied fasting lipoprotein metabolism in an FHBL subject heterozygous for a mutation causing a truncated apoB, apoB-80. Design and Methods: Very low density lipoprotein (VLDL)-, intermediate density lipoprotein (IDL)-, and low density lipoprotein (LDL)-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. Results: Compared with lean normolipidemic controls the apoB-80 FHBL subject had an elevated VLDL-apoB fractional catabolic rate and lower LDL production. ApoB production rates and IDL- and LDL-apoB fractional catabolic rates were not different. Conclusion: FHBL subjects heterozygous for a mutation truncating apoB to 80% of full-length are able to produce VLDL-apoB normally, but have rapid clearance of these particles, resulting in low levels of circulating apoB. (C) 2016 The Canadian Society of Clinical Chemists. Published by ELSEVIER. All rights reserved.
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Genetic Abetalipoproteinaemia and Hypobetalipoproteinaemia
Dyslipidemias, 2015Co-Authors: Amanda J. Hooper, John R. BurnettAbstract:The monogenic hypocholesterolaemic lipid disorders are classified depending on the lipid biochemical phenotype, gene involved, and mode of inheritance of the condition, together with the severity of the mutation or mutations present. These disorders may or may not be associated with clinical manifestations such as fat malabsorption, growth failure, fat-soluble vitamin deficiency, fatty liver disease, and neuro-ophthalmological dysfunction. We have reviewed the molecular basis, pathogenesis, and clinical aspects of these disorders of apolipoprotein (apo) B production and catabolism, focusing on abetalipoproteinaemia, familial hypobetalipoproteinaemia, and chylomicron retention disease.
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Update on Primary Hypobetalipoproteinemia
Current Atherosclerosis Reports, 2014Co-Authors: Amanda J. Hooper, John R. BurnettAbstract:“Primary Hypobetalipoproteinemia” refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low-density lipoprotein cholesterol and apolipoprotein B in plasma. Abetalipoproteinemia and homozygous familial Hypobetalipoproteinemia, although caused by mutations in different genes, are clinically indistinguishable. A framework for the clinical follow-up and management of these two disorders has been proposed recently, focusing on monitoring of growth in children and preventing complications by providing specialized dietary advice and fat-soluble vitamin therapeutic regimens. Other recent publications on familial combined hypolipidemia suggest that although a reduction of angiopoietin-like 3 activity may improve insulin sensitivity, complete deficiency also reduces serum cholesterol efflux capacity and increases the risk of early vascular atherosclerotic changes, despite low low-density lipoprotein cholesterol levels. Specialist laboratories offer exon-by-exon sequence analysis for the molecular diagnosis of primary Hypobetalipoproteinemia. In the future, massively parallel sequencing of panels of genes involved in dyslipidemia may play a greater role in the diagnosis of these conditions.
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Postprandial lipoprotein metabolism in familial Hypobetalipoproteinemia.
The Journal of Clinical Endocrinology & Metabolism, 2007Co-Authors: Amanda J. Hooper, K. Robertson, P. Hugh R. Barrett, Klaus G. Parhofer, Frank M. Van Bockxmeer, John R. BurnettAbstract: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 (
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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 (
Patrizia Tarugi - One of the best experts on this subject based on the ideXlab platform.
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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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The Janus-faced manifestations of homozygous familial Hypobetalipoproteinemia due to apolipoprotein B truncations.
Journal of Clinical Lipidology, 2015Co-Authors: Enza Di Leo, Tuba F. Eminoglu, Lucia Magnolo, Musa Gökalp Bolkent, Leyla Tümer, İlyas Okur, Patrizia TarugiAbstract:Abstract Familial Hypobetalipoproteinemia is a codominant disorder characterized by low plasma levels of low-density lipoprotein cholesterol and apolipoprotein B (apoB), which in ∼50% of the cases is due to mutations in APOB gene. In most cases, these mutations cause the formation of truncated apoBs of various sizes, which have a reduced capacity to bind lipids and form lipoprotein particles. Here, we describe 2 children with severe Hypobetalipoproteinemia found to be homozygous for novel APOB gene mutations. The first case (HBL-201) was an asymptomatic 13-year-old boy incidentally found to have slightly elevated serum transaminases associated with hepatic steatosis. He was homozygous for a truncated apoB (2211 amino acids, apoB-48.74) whose size is similar to that of wild-type apoB-48 (2152 amino acids) produced by the intestine. ApoB-48.74 is expected to be incorporated into chylomicrons in the intestine but might have a reduced capacity to form secretion-competent very low–density lipoprotein in the liver. The second patient (HBL-96) was a 6-month-old girl suspected to have abetalipoproteinemia, for the presence of chronic diarrhea, failure to thrive, extremely severe Hypobetalipoproteinemia, and low plasma levels of vitamin E and vitamin A. She was homozygous for a nonsense mutation (Gln513*) resulting in a short truncated apoB (apoB-11.30), which is not secreted into the plasma. In this patient, the impaired chylomicron formation is responsible for the severe clinical manifestations and growth retardation. In homozygous familial Hypobetalipoproteinemia, the capacity of truncated apoBs to form chylomicrons is the major factor, which affects the severity of the clinical manifestations.
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novel mutations in sar1b and mttp genes in tunisian children with chylomicron retention disease and abetalipoproteinemia
Gene, 2013Co-Authors: Lucia Magnolo, Mohamed Najah, Tatiana Fancello, E Pinotti, Ines Brini, Neji M Gueddiche, S Calandra, Naceur M Slimene, Patrizia TarugiAbstract:Abstract Monogenic Hypobetalipoproteinemias include three disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) with recessive transmission and familial Hypobetalipoproteinemia (FHBL) with dominant transmission. We investigated three unrelated Tunisian children born from consanguineous marriages, presenting Hypobetalipoproteinemia associated with chronic diarrhea and retarded growth. Proband HBL-108 had a moderate Hypobetalipoproteinemia, apparently transmitted as dominant trait, suggesting the diagnosis of FHBL. However, she had no mutations in FHBL candidate genes (APOB, PCSK9 and ANGPTL3). The analysis of MTTP gene was also negative, whereas SAR1B gene resequencing showed that the patient was homozygous for a novel mutation (c.184G>A), resulting in an amino acid substitution (p.Glu62Lys), located in a conserved region of Sar1b protein. In the HBL-103 and HBL-148 probands, the severity of Hypobetalipoproteinemia and its recessive transmission suggested the diagnosis of ABL. The MTTP gene resequencing showed that probands HBL-103 and HBL-148 were homozygous for a nucleotide substitution in the donor splice site of intron 9 (c.1236+2T>G) and intron 16 (c.2342+1G>A) respectively. Both mutations were predicted in silico to abolish the function of the splice site. In vitro functional assay with splicing mutation reporter MTTP minigenes showed that the intron 9 mutation caused the skipping of exon 9, while the intron 16 mutation caused a partial retention of this intron in the mature mRNA. The predicted translation products of these mRNAs are non-functional truncated proteins. The diagnosis of ABL and CMRD should be considered in children born from consanguineous parents, presenting chronic diarrhea associated with Hypobetalipoproteinemia.
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Novel missense variants in LCAT and APOB genes in an Italian kindred with familial lecithin:cholesterol acyltransferase deficiency and Hypobetalipoproteinemia
Journal of Clinical Lipidology, 2012Co-Authors: Paola Conca, Patrizia Tarugi, Lucia Magnolo, Silvana Pileggi, Sara Simonelli, Emanuela Boer, Giuliano Boscutti, Silvana Penco, Guido Franceschini, Laura CalabresiAbstract:Background Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of very-low-density lipoproteins and low-density lipoprotein (LDL). Mutations of APOB gene cause familial Hypobetalipoproteinemia, a codominant disorder characterized by low plasma levels of LDL cholesterol and apoB. Objective This was a genetic and biochemical analysis of an Italian kindred with Hypobetalipoproteinemia whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease. Methods Plasma lipids and apolipoproteins, cholesterol esterification, and high-density lipoprotein (HDL) subclass distribution were analyzed. LCAT and APOB genes were sequenced. Results The proband had severe impairment of plasma cholesterol esterification and high preβ-HDL content. He was heterozygote for the novel LCAT P406L variant, as were two other family members. The proband's wife and children presented with familial Hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely attributable to the low amount of circulating LDL. After renal transplantation, proband's lipid profile, HDL subclass distribution, and plasma cholesterol esterification were almost at normal levels, suggesting a mild contribution of the LCAT P406L variant to his pretransplantation severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification. Conclusion LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution, and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial Hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.
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Plasma non-cholesterol sterols in primary Hypobetalipoproteinemia.
Atherosclerosis, 2011Co-Authors: Davide Noto, Patrizia Tarugi, Pin Yue, Angelo B. Cefalù, Giacoma Barraco, Francesca Fayer, Mariangela Mina, Gustav Schonfeld, Maurizio AvernaAbstract:Primary Hypobetalipoproteinemia (pHBL) is characterized by plasma cholesterol levels ApoB48, and FHBL harbouring as yet unknown molecular defects. Not linked FHBL kindred are not homogeneous in terms of plasma NCS levels. NCS cannot replace genetic HBL analysis.