M.685 Liver dysfunction in a man with HFE C282Y/H63D, α1-antitrypsin PIZ, and familial hypobetalipoproteinaemia

Whitfield, A. G. W.; Robertson, K; Barrett, Patrick R.; Bockxmeer, F. van; Burnett, John R.

doi:10.1016/s1567-5688(04)90683-1

Cited by 2 publications

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“…Familial liganddefective apoB-100 (OMIM 144010), an autosomal co-dominant form of hypercholesterolemia, is the only other phenotype to have been associated with naturally occurring missense mutations in APOB (i.e. the R3500Q, R3500W, R3531C, R3480W, and H3543Y variants) (28,55,56). The diseases caused by these point mutations within the coding sequences of APOB demonstrate the key role that apoB-100 plays in regulating VLDL assembly/secretion and receptor-mediated endocytosis of LDL.…”

Section: Discussionmentioning

confidence: 99%

“…7 Previous cell culture studies with a variety of truncated apoB forms (ranging from apoB-15 to apoB-94) showed that most of the C-terminally truncated apoB forms were secreted as efficiently as normal apoB-100 or apoB-48 (39,63). Thus, it is rather unusual that substitution of Leu 343 with Val, both being hydrophobic and differing merely a methylene group that should have a much less severe impact than C-terminal truncations of apoB (27,28,30), can cause FHBL. In addition to decreased secretion, increased catabolism of apoB-containing lipoproteins has been implicated in causing the FHBL lipid phenotype (64 -68).…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygotes are usually asymptomatic with LDL cholesterol and apoB-100 concentrations Ͻ50% of those in normal plasma. Homozygotes have undetectable plasma LDL cholesterol and apoB, and their clinical presentation, depending on the specific mutation, varies from no symptoms to severe gastrointestinal and neurological dysfunction, similar to that in abetalipoproteinemia (27,28,30). Nonsense, frameshift, and splicing mutations in the APOB gene leading to formation of prematurely truncated apoB species have been reported in FHBL subjects (27)(28)(29)(30).…”

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confidence: 99%

“…Familial hypobetalipoproteinemia (FHBL; OMIM 107730) is a genetically heterogeneous autosomal co-dominant disorder characterized by low levels (Ͻ5th percentile for age and sex) of plasma apoB-containing lipoproteins (27)(28)(29)(30). It has been suggested that FHBL represents a longevity syndrome (31) and might be associated with cardiovascular protection because of resistance to atherosclerosis (32).…”

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Missense Mutations in APOB within the βα1 Domain of Human APOB-100 Result in Impaired Secretion of ApoB and ApoB-containing Lipoproteins in Familial Hypobetalipoproteinemia

Burnett

Zhong

Jiang

et al. 2007

Journal of Biological Chemistry

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Here we identified a second nonsynonymous APOB mutation, L343V, in another FHBL kindred. Heterozygotes for L343V (n ‫؍‬ 10) had a mean plasma apoB at 0.31 g/liter as compared with 0.80 g/liter in unaffected family members (n ‫؍‬ 22). The L343V mutation impaired secretion of apoB-100 and very low density lipoproteins. The secretion efficiency was 20% for B100wt and 10% for B100LV and B100RW. Decreased secretion of mutant apoB-100 was associated with increased endoplasmic reticulum retention and increased binding to microsomal triglyceride transfer protein and BiP. Reduced secretion efficiency was also observed with B48LV and B17LV. Biochemical and biophysical analyses of apoB domain constructs showed that L343V and R463W altered folding of the ␣-helical domain within the N terminus of apoB. Thus, proper folding of the ␣-helical domain of apoB-100 is essential for efficient secretion. Apolipoprotein (apo)6 B, a large amphipathic glycoprotein, plays a central role in human lipoprotein metabolism (1, 2). The human apoB gene (APOB) is located on chromosome 2 and produces, via a unique mRNA editing process (3), two forms of apoB, namely apoB-48 (2152 amino acids) and apoB-100 (4536 amino acids) (4, 5). ApoB-48 is the truncated form of apoB-100 consisting of the N-terminal 48% of full-length apoB-100. ApoB-48 is synthesized in the intestine and is essential for the formation and secretion of chylomicrons. ApoB-100 is synthesized in the liver and is an essential structural component of very low density lipoprotein (VLDL) and its metabolic products, intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), and is also a ligand for the LDL receptor. Unlike humans, the rat liver produces both apoB-100 and apoB-48, and both forms can assemble VLDL (6).A pentapartite model for human apoB-100 has been proposed, which depicts a five-domain structure composed of alternating amphipathic ␣-helices and amphipathic ␤-strands, namely ␤␣1-␤1-␣2-␤2-␣3 (7). The ␤␣1 domain is a mixture of 13 amphipathic ␤-strands and 17 amphipathic ␣-helices, whose amino acids share extensive sequence homologies to the yolk protein lipovitellin (7-9). The apoB ␤␣1 domain has been modeled on the structure of silver lamprey lipovitellin, in which the 13 ␤-strands (amino acids 21-263) form a ␤-barrel, whereas the 17 ␣-helices (amino acids 440 -592) form a two-layered helical bundle (10). There is an interface between the ␣-helical bundle * This work was supported by the Heart and Stroke Foundation of Ontario . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Missense Mutations in APOB within the βα1 Domain of Human APOB-100 Result in Impaired Secretion of ApoB and ApoB-containing Lipoproteins in Familial Hypobetalipoproteinemia

Burnett

Zhong

Jiang

et al. 2007

Journal of Biological Chemistry

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“…Apolipoprotein B (apoB) 3 is a ϳ540-kDa protein in chylomicrons and very low (VLDL) and low density (LDL) lipoproteins, the atherogenic particles secreted from the liver and small intestine. With the aid of microsomal triglyceride transfer protein (MTP), lipids are added co-translationally to apoB in the endoplasmic reticulum (ER), which results in the formation of a primordial lipoprotein (1,2).…”

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confidence: 99%

The Hsp110 Molecular Chaperone Stabilizes Apolipoprotein B from Endoplasmic Reticulum-associated Degradation (ERAD)

Hrizo

Gusarova

Habiel

et al. 2007

Journal of Biological Chemistry

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Apolipoprotein B (apoB) is the most abundant protein in low density lipoproteins and plays key roles in cholesterol homeostasis. The co-translational degradation of apoB is controlled by fatty acid levels in the endoplasmic reticulum (ER) and is mediated by the proteasome. To define the mechanism of apoB degradation, we employed a cell-free system in which proteasomedependent degradation is recapitulated with yeast cytosol, and we developed an apoB yeast expression system. We discovered that a yeast Hsp110, Sse1p, associates with and stabilizes apoB, which contrasts with data indicating that select Hsp70s and Hsp90s facilitate apoB degradation. However, the Ssb Hsp70 chaperones have no effect on apoB turnover. To determine whether our results are relevant in mammalian cells, Hsp110 was overexpressed in hepatocytes, and enhanced apoB secretion was observed. This study indicates that chaperones within distinct complexes can play unique roles during ER-associated degradation (ERAD), establishes a role for Sse1/Hsp110 in ERAD, and identifies Hsp110 as a target to lower cholesterol.

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M.685 Liver dysfunction in a man with HFE C282Y/H63D, α1-antitrypsin PIZ, and familial hypobetalipoproteinaemia

Cited by 2 publications

References 0 publications

Missense Mutations in APOB within the βα1 Domain of Human APOB-100 Result in Impaired Secretion of ApoB and ApoB-containing Lipoproteins in Familial Hypobetalipoproteinemia

Missense Mutations in APOB within the βα1 Domain of Human APOB-100 Result in Impaired Secretion of ApoB and ApoB-containing Lipoproteins in Familial Hypobetalipoproteinemia

The Hsp110 Molecular Chaperone Stabilizes Apolipoprotein B from Endoplasmic Reticulum-associated Degradation (ERAD)

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