A form of familial hypobetalipoproteinaemia not due to a mutation in the apolipoprotein B gene

Fazio, Sergio; Sidoli, Alessandro; Vivenzio, A.; Maietta, A.; Giampaoli, Simona; Menotti, Alessandro; Antonini, R; Urbinati, G; Baralle, Francisco E.; Ricci, Giorgio

doi:10.1111/j.1365-2796.1991.tb00304.x

Cited by 32 publications

(20 citation statements)

References 19 publications

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“…42 To what extent are the apoE2 homozygosity and the apoB truncation contributing to low total and LDL cholesterol concentrations in our subjects? The apoE2/E2 genotype is consistently associated with an O^/L reduction in mean total plasma cholesterol concentrations in general populations, 7 and even in hypobetalipoproteinemic subjects, a small but significant reduction of apoB was noted in apoE2/E2 subjects compared with other apoE phenotypes. 43 The <5th percentile total and LDL cholesterol levels and the =30% of normal apoB levels in our proband and his son are much lower than those seen in apoE2 homozygotes without any truncations of apoB but not significantly different from the very low mean total plasma or LDL cholesterol and apoB concentrations of our FHBL populations with truncated apoBs who are not apoE2 homozygotes.…”

Section: Discussionmentioning

confidence: 96%

Dysbetalipoproteinemia in a kindred with hypobetalipoproteinemia due to mutations in the genes for ApoB (ApoB-70.5) and ApoE (ApoE2).

Groenewegen

Krul

Averna

et al. 1994

Arterioscler Thromb

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We identified the first insertion mutation that specifies an apolipoprotein (apo)B truncation, apoB-70.5, in a father and son with hypobetalipoproteinemia (total and lowdensity lipoprotein [LDL] cholesterol <5th percentile, plasma apoB levels approximately one third of normal). The mutation is due to insertion of an adenine (A) into a 7-A repeat between cDNA position 9754 and 9760 of the apoB gene, resulting in a frame shift of 13 new amino acids and a termination codon at amino acid residue 3197. The DNA mutation cosegregated with the apoB truncation and hypobetalipoproteinemia in the kindred. The two apoB-70_5/apoB-100 heterozygotes also are apoE2 homozygotes by genotyping; /3-very-low-density lipoprotein (VLDL) was present, and VLDL cholesterol/trigh/ceride ratios were increased (0.29) in the plasmas of both. Density gradient ultracentrifugation and gel filtration chromatography profiles showed increased amounts of particles in the F amilial hypobetalipoproteinemia (FHBL) is characterized by plasma total and low-density lipoprotein (LDL) cholesterol concentrations below the 5th percentile (<3.9 mmol/L). Truncation specifying mutations of the apolipoprotein (apo)B gene account for a minority of these cases.1 To date, all these mutations have been deletion or nonsense mutations, 1 leading to decreased production or increased clearance of apoB-containing lipoproteins, 2 -3 perhaps due to factors involved in gene regulation or mRNA stability/ Mutations that specify truncations shorter than apoB-25 are not detectable in plasma. 56 However, in some cases of FHBL where no truncated apoB protein can be detected in plasma, haplotype analysis also failed to show linkage of FHBL with the apoB gene (W.A. Groenewegen, unpublished, and Reference 7), suggesting that other genes besides the apoB gene may be responsible for the FHBL phenotype.The apoE present on very-low-density lipoprotein (VLDL) and chylomicron remnants is primarily respon- Two populations of LDL were present. ApoB-70.5 was primarily associated with LDL particles of higher density and of smaller size than the LDL particles containing apoB-100. ApoB-48-containing particles were present in the VLDL of fasting plasmas of both subjects, and the postprandial levels of chylomicrons and remnants as measured by the vitamin A fat tolerance test were increased. In conclusion, both subjects heterozygous for apoB-70.5 and homozygous for apoE2 showed the classic characteristics of dysbetalipoproteinemia superimposed onto the hypolipoproteinemic state. 8 The apoE3 isoform is the most common and is defined as the wild type. ApoE4 is associated with increased LDL receptor binding and, on average, apoE4 homozygotes have higher than average total and LDL cholesterol levels, probably due to downregulation of their LDL receptors. ApoE2 displays severely reduced LDL and remnant receptor binding, and on average apoE2 homozygotes have low total and LDL cholesterol levels, probably due to upregulation of LDL receptors.9 ' 10 Despite lower than average total cholesterol l...

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Section: Discussionmentioning

confidence: 96%

Dysbetalipoproteinemia in a kindred with hypobetalipoproteinemia due to mutations in the genes for ApoB (ApoB-70.5) and ApoE (ApoE2).

Groenewegen

Krul

Averna

et al. 1994

Arterioscler Thromb

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“…8,9 An interesting finding in the F kindred was the presence of very low levels of HDL cholesterol and apoA-I in some, but not all, affected subjects. Some affected hypobetalipoproteinemia subjects in the family described by Fazio et al 13 have similarly low HDL cholesterol and apoA-I levels. By contrast, in typical FHBL caused by apoB gene mutations, levels of HDL and apoA-I are normal in affected subjects.…”

Section: Elias Et Al Metabolism Of Triglycerides and Apob-100 In Fhblmentioning

confidence: 99%

“…9 -12 However, in 2 reported FHBL families, such truncations are not present in plasma, and the disorder is not linked to the apoB gene. 13,14 The genetic and metabolic bases of these cases of FHBL remain unknown.We have reported on a 40-member FHBL kindred in which the hypobetalipoproteinemia phenotype segregates as an autosomal-dominant trait, but no apoB truncations were …”

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confidence: 99%

In Vivo Metabolism of ApoB, ApoA-I, and VLDL Triglycerides in a Form of Hypobetalipoproteinemia Not Linked to the ApoB Gene

Elias

Patterson

Schonfeld

2000

ATVB

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Abstract-Familial hypobetalipoproteinemia (FHBL) is an autosomal codominant disorder that may result from different mutations in the apolipoprotein B (apoB) gene or chromosome 2. However, linkage of FHBL to the apoB gene was ruled out in 2 kindreds reported to date, and the genetic and metabolic bases for FHBL remain unknown. One of the reported kindreds is our 40-member F kindred, in which we found linkage of FHBL to a novel susceptibility region on chromosome 3p21.1-2. In addition to having low apoB levels, some, but not all, of the affected subjects in the F kindred also had low levels of high density lipoprotein (HDL) cholesterol and apoA-I. Our aim was to define the metabolic bases of the disorder in the F kindred. Therefore, we studied the in vivo kinetics of apoB and apoA-I and very low density lipoprotein (VLDL) triglycerides in 4 affected subjects and 5 normolipidemic relatives. Deuterated leucine and deuterated glycerol were used to label the apolipoproteins and triglycerides, respectively. Compartmental modeling was used to obtain the kinetic parameters. Affected subjects had (1) A polipoprotein B plays a crucial role in the intracellular assembly and secretion of triglyceride-rich lipoproteins and is a ligand for the LDL receptor. 1 High plasma levels of apoB are directly correlated with the risk of atherosclerotic coronary artery disease. 2 ApoB exists in plasma in 2 forms, apoB-100 secreted by the liver in VLDL particles and apoB-48 secreted by the intestine in chylomicrons. Both forms are the products of a single apoB gene located on chromosome 2. 1 ApoB-48 results from a tissue-specific apoB mRNA editing process in the intestine, which allows translation of 48% of the amino terminal of apoB-100. Three inherited syndromes characterized by low plasma levels of apoB have been described: (1) Abetalipoproteinemia, in which apoB-containing lipoproteins are nearly absent from plasma, is inherited as an autosomal-recessive disorder. It is caused by mutations in the microsomal triglyceride transfer protein (MTP) gene. 3 (2) Chylomicron retention disease, a disorder that selectively affects chylomicron secretion by the intestine, is also inherited as an autosomal-recessive trait, but its molecular etiology has not been identified. 4 (3) Familial hypobetalipoproteinemia (FHBL) is inherited as an autosomal-dominant trait, with heterozygotes having apoB and LDL cholesterol levels below the fifth percentile. Although the molecular cause in most cases is unknown, 5,6 FHBL can result from 1 of several mutations in the apoB gene that produce truncated forms of apoB. 7,8 Low plasma levels of apoB in these cases are caused by decreased secretion rates of the truncated and the normal apoB-100 forms of apoB and in some cases by enhanced catabolism of the truncationcontaining lipoproteins. 9 -12 However, in 2 reported FHBL families, such truncations are not present in plasma, and the disorder is not linked to the apoB gene. 13,14 The genetic and metabolic bases of these cases of FHBL remain unknown.We have reported o...

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“…Such individuals may actually be protected from atherosclerotic disease and may show an increased longevity ( 1). This disorder has been described in dozens of cases (3)(4)(5); The heterozygous form of familial hypobetalipoproteinemia has been estimated to affect as muchas 0.1 to 0.8 percent of the population (6,7). To our knowledge, however, this is the first report to describe a case of familial hypobetalipoproteinemia complicated by hypothyroidism.…”

Section: Introductionmentioning

confidence: 66%

“…The molecular defect in the present patient's apo B gene, if it exists, may be affected by apo B metabolism. However, a case of familial hypobetalipoproteinemia that did not arise from a mutation in the apo B gene has been reported (5). In another case of hypobetalipoproteinemia, in which plasma apo B was detectable and was of normal size, the increased hepatic catabolism was responsible for its low concentration and was secondary to the constitutionally enhanced synthesis of bile acid (19).…”

Section: Case Report Case Historymentioning

confidence: 99%

Familial Hypobetalipoproteinemia Associated with Hypothyroidism.

et al. 1995

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A 55-year-old Japanese womanwith familial hypobetalipoproteinemia associated with hypothyroidism was admitted to the hospital because of orthopnea and congestive heart failure. Thyroid function testing revealed hypothyroidism, but she exhibited low levels of serum cholesterol (111 mg/dl) and apolipoprotein (apo) B (48.5 mg/dl). No abnormal bands were detected with gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis of very low density lipoprotein, low density lipoprotein and high density lipoprotein followed by immunoblotting with anti apo B polyclonal antibody. In this case, apo B structural abnormality could not be identified. (Internal Medicine 34: 879-882, 1995)

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A form of familial hypobetalipoproteinaemia not due to a mutation in the apolipoprotein B gene

Cited by 32 publications

References 19 publications

Dysbetalipoproteinemia in a kindred with hypobetalipoproteinemia due to mutations in the genes for ApoB (ApoB-70.5) and ApoE (ApoE2).

Dysbetalipoproteinemia in a kindred with hypobetalipoproteinemia due to mutations in the genes for ApoB (ApoB-70.5) and ApoE (ApoE2).

In Vivo Metabolism of ApoB, ApoA-I, and VLDL Triglycerides in a Form of Hypobetalipoproteinemia Not Linked to the ApoB Gene

Familial Hypobetalipoproteinemia Associated with Hypothyroidism.

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