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

Burnett, John R.; Shan, Jing; Miskie, Brooke A; Whitfield, Amanda; Yuan, Jane; Tran, Khai; McKnight, C. James; Hegele, Robert A.; Yao, Zemin

doi:10.1074/jbc.m300235200

Cited by 84 publications

(79 citation statements)

References 56 publications

(39 reference statements)

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“…Unlike heterozygous FHBL, homozygous FHBL is characterized by absence, or extremely low levels, of apoB-containing lipoproteins and acanthocytic red blood cells 22 and can manifest clinically in neurological dysfunction, 23 but not always. 24 The index patient was grossly neurologically normal, but had about 17% acanthocytes on blood film, a paranoid psychosis and lower levels of LDL-cholesterol than those previously described in heterozygous FHBL. [24][25][26][27] Heterozygous FHBL subjects, such as the index patient, typically have low plasma concentrations of vitamin E (Table 1).…”

Section: Discussionmentioning

confidence: 79%

“…24 The index patient was grossly neurologically normal, but had about 17% acanthocytes on blood film, a paranoid psychosis and lower levels of LDL-cholesterol than those previously described in heterozygous FHBL. [24][25][26][27] Heterozygous FHBL subjects, such as the index patient, typically have low plasma concentrations of vitamin E (Table 1). 28 Vitamin E is essential for neurological function and is transported in plasma in association with the apoB-containing lipoproteins.…”

Section: Discussionmentioning

confidence: 79%

“…However, increased violent behavior in heterozygous FHBL has not been reported before, which suggests that the association between apoB-29.4 and violent behavior is specific to this particular apoB mutation in much the same way that neurological dysfunction is associated with particular homozygous FHBL mutations and not others. 23,24 The fecundity of members of the index patient's immediate prior paternal generation that carried apoB-29.4 or had committed suicide (II:1, II:4, II:6, II:9) was low, an average of one child each, compared to the remainder (II:2, II:3, II:5, II:7, II:8), an average of two children each. However, the grandfather, an obligate heterozygote for apoB-29.4, had nine children.…”

Section: Discussionmentioning

confidence: 99%

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Violent behavior associated with hypocholesterolemia due to a novel APOB gene mutation

et al. 2006

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A 26-year-old male, the index patient, presented with persecutory delusions and suicidal behavior. He had 10 paternal male relatives in two prior generations. Five of them died by violent suicide and one, of the five, also committed a double homicide. The index patient was found to be hypocholesterolemic due to being heterozygous for a novel mutation of apolipoprotein B (apoB-29.4). His mother and paternal grandmother were normocholesterolemic, whereas a surviving paternal uncle was hypocholesterolemic and heterozygous for the apoB-29.4 mutation. This indicated that the index patient's father and paternal grandfather, both of which died by violent suicide, were obligate heterozygotes for the apoB-29.4 mutation and that the index patient inherited the mutation from his paternal grandfather. The odds ratio for the association between hypocholesterolemia and violent behavior in this family, where cholesterol status was known, was 16.9 (95% confidence interval 1.1-239.3). Therefore, our results support an inheritable relationship between violent behavior and hypocholesterolemia.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Violent behavior associated with hypocholesterolemia due to a novel APOB gene mutation

et al. 2006

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“…Naturally occurring gene mutations in affected families have been useful in identifying important domains of apoB (35). Four years ago, we discovered the first missense mutation in APOB causing FHBL, namely R463W, in a Christian Lebanese kindred (35). The R463W mutation specified a local domain that appeared to be critical for the efficient secretion of apoB and for lipid recruitment during lipoprotein assembly.…”

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confidence: 99%

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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“…5,6 Only a single amino acid substitution (R463W) has been reported so far as the cause of FHBL. 7 In some kindred, FHBL is linked to loci on chromosomes 3 (3p21) and 13 (13q) but the genes involved have not been identified yet. 8 Recently, PCSK9 gene has emerged as an important candidate gene for FHBL.…”

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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

123

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

Cited by 84 publications

References 56 publications

Violent behavior associated with hypocholesterolemia due to a novel APOB gene mutation

Violent behavior associated with hypocholesterolemia due to a novel APOB gene mutation

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

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

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