A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5)

Tarugi, Patrizia; Lonardo, Amedeo; Ballarini, G.; Erspamer, Laura; Tondelli, E; Bertolini, Stefano; Calandra, Sebastiano

doi:10.1016/s0168-8278(00)80270-6

Cited by 54 publications

(28 citation statements)

References 49 publications

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“…3E). There is evidence that the hepatobiliary system can be affected in FHBL, with steatosis reported in several kindreds (52)(53)(54). The elevated serum transaminases and ferritin in the R463W heterozygotes could represent a subclinical phenotype that is consistent with such previous observations.…”

Section: Aspsupporting

confidence: 85%

A Novel Nontruncating APOB Gene Mutation, R463W, Causes Familial Hypobetalipoproteinemia

Burnett

Shan

Miskie

et al. 2003

Journal of Biological Chemistry

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Familial hypobetalipoproteinemia (FHBL), an autosomal co-dominant disorder, is associated with reduced plasma concentrations (<5th percentile for age and sex) of apolipoprotein (apo) B and ␤-migrating lipoproteins. To date, only mutations in APOB encoding prematurely truncated apoB have been found in FHBL. We discovered a novel APOB gene mutation, namely R463W, in an extended Christian Lebanese FHBL kindred. Heterozygotes for R463W had the typical FHBL phenotype, whereas homozygotes had barely detectable apoB-100. The effect of the R463W mutation on apoB secretion was examined using transfected McA-RH7777 cells that expressed one of two recombinant human apoBs, namely B48 and B17. In both cases, the mutant proteins (B48RW and B17RW) were retained within the endoplasmic reticulum and were secreted poorly compared with their wild-type counterparts. Pulse-chase analysis showed that secretion efficiencies of B48RW and B17RW were, respectively, 45 and 40% lower than those of the wild-types. Substitution of Arg 463 with Ala in apoB-17 (B17RA) decreased secretion efficiency by ϳ50%, but substitution with Lys (B17RK) had no effect on secretion, indicating that the positive charge was important. Molecular modeling of apoB predicted that Arg 463 was in close proximity to Glu 756 and Asp 456 . Substitution of Glu 756 with Gln (B17EQ) had no effect on secretion, but substitution of Asp 456 with Asn (B17DN) decreased secretion to the same extent as B17RW. In co-transfection experiments, the mutant B17RW showed increased binding to microsomal triglyceride transfer protein as compared with wild-type B17. Thus, the naturally occurring R463W mutant reveals a key local domain governing assembly and secretion of apoBcontaining lipoproteins. Apolipoprotein (apo)1 B is essential for the formation of triglyceride-rich lipoproteins, namely very low density lipoproteins (VLDL) and chylomicrons (1). In humans, the liver secretes full-length apoB-100 containing 4536 amino acids, whereas the intestine secretes apoB-48 consisting of the aminoterminal 48% of apoB-100 (2). Both forms of apoB are encoded by the APOB gene on chromosome 2, which spans 43 kb and contains 29 exons coding for a 14-kb mRNA (3, 4). ApoB-48 arises from a unique editing process in which cytosine at nucleotide position 6666 is converted to uracil, thereby generating an in-frame stop codon (5). The rat liver produces both apoB-100 and apoB-48, and both forms can assemble VLDL (6).A pentapartite model for apoB-100 on low density lipoproteins (LDL) has been proposed, in which the apoB polypeptide can be divided into five structurally distinct domains, namely NH 2 -␤␣1-␤1-␣2-␤2-␣3-COOH (7). The amino acid sequence of the ␤␣1 domain is homologous to lamprey lipovitellin and microsomal triglyceride transfer protein (MTP) (8,9). The ␤␣1 domain of human apoB has thus been modeled on the basis of the solved lipovitellin structure, in which 13 ␤-strands (amino acids 21-263) form a ␤ barrel, followed by a two-layered helical bundle consisting of 17 ␣-helices (amino acids 294 -592...

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Section: Aspsupporting

confidence: 85%

A Novel Nontruncating APOB Gene Mutation, R463W, Causes Familial Hypobetalipoproteinemia

Burnett

Shan

Miskie

et al. 2003

Journal of Biological Chemistry

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“…3,4 These subjects were recruited in various geographic area of Italy. In all of them, the criteria for the diagnosis of FHBL were the plasma level of LDL-C and apoB below 5th percentile of the distribution in the population and the exclusion of secondary forms of hypolipidemia.…”

Section: Fhbl Subjectsmentioning

confidence: 99%

“…1 FHBL heterozygotes may be asymptomatic (they are often identified through population screening for low-plasma cholesterol) 2 or have clinical manifestations (fatty liver disease and intestinal fat malabsorption), which require medical intervention. [3][4][5] FHBL may or may not be linked to the APOB gene. Most mutations in APOB gene prevent the complete translation of apoB mRNA, leading to truncated apoBs of various size that may or may not be secreted into the plasma.…”

mentioning

confidence: 99%

A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol

Fasano

Cefalù

Leo

et al. 2007

ATVB

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124

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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 AfricanAmericans 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 (Ͻ5 th ) percentile, 44 in the highest (Ͼ95 th ) percentile, and 100 with the average plasma cholesterol derived from general population. In one familial hypobetalipoproteinemia kindred and in 2 hypocholesterolemic blood donors we found a novel PCSK9 mutation in exon 1 (c.202delG) resulting in a truncated peptide (Ala68fsLeu82X). Two familial hypobetalipoproteinemia subjects and 4 hypocholesterolemic blood donors were carriers of the R46L substitution previously reported to be associated with reduced low-density lipoprotein cholesterol as well as other rare amino acid changes (T77I, V114A, A522T and P616L) not found in the other groups examined. Conclusions-We discovered a novel inactivating mutation as well as some rare nonconservative amino acid substitutions of PCSK9 in white hypocholesterolemic individuals.

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“…15 Hepatic steatosis is a well-documented histological feature during hepatitis C virus (HCV) infection. [16][17][18][19] There is clear evidence that HCV itself (through its core protein) causes steatosis both in transgenic animal models and in vitro cell lines.…”

mentioning

confidence: 99%

Concluding remarks: metabolic syndrome, liver and HCV

Cortez‐Pinto

2005

Aliment Pharmacol Ther

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A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5)

Cited by 54 publications

References 49 publications

A Novel Nontruncating APOB Gene Mutation, R463W, Causes Familial Hypobetalipoproteinemia

A Novel Nontruncating APOB Gene Mutation, R463W, Causes Familial Hypobetalipoproteinemia

A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol

Concluding remarks: metabolic syndrome, liver and HCV

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