Other entities represented in this entry:
HGNC Approved Gene Symbol: APOB
SNOMEDCT: 238040008, 238081000, 442411007, 60193003; ICD10CM: E78.2, E78.6;
Cytogenetic location: 2p24.1 Genomic coordinates (GRCh38): 2:21,001,429-21,044,073 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p24.1 | Hypercholesterolemia, familial, 2 | 144010 | Autosomal dominant | 3 |
| Hypobetalipoproteinemia | 615558 | Autosomal recessive | 3 |
Apolipoprotein B is the main apolipoprotein on chylomicrons and low density lipoproteins (LDLs). It occurs in the plasma in 2 main forms, apoB48 and apoB100. The first is synthesized exclusively by the intestine, the second by the liver (summary by Law et al., 1985).
Lusis et al. (1985) identified cDNA clones for rat liver apoB. Law et al. (1985) cloned human APOB.
Deeb et al. (1986) found that APOB RNA isolated from monkey small intestine contained sequences homologous to the cDNA of apolipoprotein B100. These results were interpreted as indicating that intestinal (B48) and hepatic (B100) forms of apoB are coded by a single gene. Glickman et al. (1986) found a single mRNA transcript for apoB regardless of the form of apoB (apoB100 or apoB48) synthesized in the liver or intestine.
Hospattankar et al. (1986) presented some immunologic data suggesting that the 2 proteins share a common carboxyl region sequence. Chen et al. (1986) determined the complete cDNA and amino acid sequence of apoB100. Knott et al. (1986) reported the primary structure of apolipoprotein B. The precursor has 4,563 amino acids; the mature apoB100 has 4,536 amino acid residues. This represents a very large mRNA of more than 16 kb. Law et al. (1986) also provided the complete nucleotide and derived amino acid sequence of apoB100 from a study of cDNA. Strong evidence that apoB100 and apoB48 are products of the same gene was provided by Young et al. (1986).
Cladaras et al. (1986) concluded from the sequence of apolipoprotein B100 that apoB48 may result from differential splicing of the same primary apoB mRNA transcript.
Hardman et al. (1987) found that mature, circulating B48 is homologous over its entire length (estimated to be between 2,130 and 2,144 amino acid residues) with the amino-terminal portion of B100 and contains no sequence from the carboxyl end of B100. From structural studies, Innerarity et al. (1987) concluded that apoB48 represents the amino-terminal 47% of apoB100 and that the carboxyl terminus of apoB48 is in the vicinity of residue 2151 of apoB100. Chen et al. (1987) deduced that human apolipoprotein B48 is the product of an intestinal mRNA with an in-frame UAA stop codon resulting from a C-to-U change in the codon CAA encoding Gln(2153) in apoB100 mRNA. The carboxyl-terminal ile-2152 of apoB48 purified from chylous ascites fluid has apparently been cleaved from the initial translation product, leaving met-2151 as the new carboxyl-terminus. The organ-specific introduction of a stop codon to an mRNA is an unprecedented finding. Only the sequence that codes B100 is present in genomic DNA. The change from CAA to UAA as codon 2153 of the message is a unique RNA editing process. Higuchi et al. (1988) reported similar findings. ApoB48 contains 2,152 residues compared to 4,535 residues in apoB100. Using a cloned rat cDNA as a probe, Lau et al. (1994) cloned cDNA and genomic sequences of the gene for the human APOB mRNA editing protein (BEDP; 600130). Expression of the cDNA in HepG2 cells resulted in editing of the intracellular apoB mRNA. By Northern blot analysis, they showed that the human BEDP mRNA is expressed exclusively in the small intestine.
Law et al. (1985) assigned the APOB gene to chromosome 2 by filter hybridization with DNA from human/mouse somatic cell hybrids.
By somatic cell hybrid studies and by in situ hybridization, Knott et al. (1985) assigned the APOB gene to the tip of 2p in band p24.
Deeb et al. (1986) used a hybridization probe to detect homologous sequences in both flow-sorted and in situ metaphase chromosomes. The gene was assigned to 2p24-p23.
From study of chromosomal aberrations in somatic cell hybrids, Huang et al. (1986) concluded that the APOB locus is located in either the 2p21-p23 or the 2pter-p24 segment. Mehrabian et al. (1986) localized APOB to 2p24-p23 by somatic cell hybridization and in situ hybridization. Filter hybridization studies with genomic DNA and with hepatic and intestinal mRNA suggested that hepatic and intestinal apoB are derived from the same gene.
Law et al. (1986) used a specific mouse monoclonal antibody, MB19, to characterize a common form of genetic polymorphism of APOB. They found that the polymorphism was expressed in a parallel manner in apoB100 and apoB48.
Law et al. (1986) found that 60 of 83 middle-aged white men had an XbaI restriction site polymorphism within the coding sequence of the apoB gene. Persons homozygous or heterozygous for the XbaI restriction site had mean serum triglyceride levels 36% higher than homozygotes without the site. Mean serum cholesterol was less strikingly elevated in those with the restriction site. The Ag system of lipoprotein antigens (see later) is known to represent polymorphism of the APOB locus. It is in strong linkage disequilibrium with the XbaI RFLP; the 2 probably reveal the same association with plasma lipids. Mehrabian et al. (1986) also identified 2 common RFLPs which should be useful in family studies.
Ludwig et al. (1989) described a hypervariable region 3-prime to the human APOB gene. By PCR amplification of the region followed by electrophoresis in a denaturing acrylamide gel, they found 14 different alleles containing 25 to 52 repeats of a 15-basepair unit in 318 unrelated individuals. Boerwinkle et al. (1989) also made observations on this variable-number-of-tandem-repeats (VNTR) polymorphism. Boehnke (1991) used the VNTR polymorphism near the APOB locus as a test case for his method of estimating allele frequency from data on relatives. He stated that there are 15 known APOB VNTR alleles and that 12 were observed in the families he studied.
By use of both pedigree linkage analysis and sib-pair linkage analysis in 23 informative families, Coresh et al. (1992) found no evidence of common APOB alleles that had a major influence on plasma levels of apoB100.
Singh et al. (2004) examined the association between the XbaI polymorphism of APOB100 and gallbladder diseases, including gallbladder cancer, in a non-Indian population in which both gallstones and gallbladder cancer are common. They found that the frequency of X- allele was significantly increased in gallbladder cancer patients with or without gallstones (odds ratio = 2.3 and 1.7, respectively). They suggested that the apoB-XbaI gene polymorphism confers susceptibility to carcinoma of the gallbladder under specific environmental conditions.
The base change in APOB that creates the XbaI site, 7673C-T, does not change the amino acid threonine at codon 2488 (T2488T). In a study comprising 9,185 individuals from the general population, 2,157 patients with ischemic heart disease (IHD), and 378 patients with ischemic cerebrovascular disease (ICVD), Benn et al. (2005) found that the APOB 7673C-T polymorphism is associated with moderate increases in total cholesterol, LDL cholesterol, and apoB in both genders in the general population, but not with risk of IHD or ICVD or with total mortality.
Benn et al. (2007) found that APOB K4154K homozygotes for the E4154K polymorphism had an age-adjusted hazard ratio of 0.4 (95% CI, 0.2-0.9) for ischemic cerebrovascular disease and 0.2 (CI, 0.1-0.7) for ischemic stroke relative to E4154E homozygotes. Furthermore, E4154K heterozygotes and K4154K homozygotes had lower levels of apolipoprotein B and LDL cholesterol, compared with E4154E homozygotes. APOB K4154K homozygosity predicted a 3- to 5-fold reduction in risk of ischemic cerebrovascular disease and ischemic stroke.
Demant et al. (1988) found a significant association between a particular RFLP of the APOB gene and the total fractional clearance rate of LDL. Presumably, this effect acts through variable binding to the LDLR and is a significant factor in the rate of catabolism of LDL.
Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs693 of APOB, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.
Teslovich et al. (2010) performed a genomewide association study for plasma lipids in more than 100,000 individuals of European ancestry and reported 95 significantly associated loci (P = less than 5 x 10(-8)), with 59 showing genomewide significant association with lipid traits for the first time. The newly reported associations included SNPs near known lipid regulators as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contributed not only to normal variation in lipid traits but also to extreme lipid phenotypes and had an impact on lipid traits in 3 non-European populations (East Asians, South Asians, and African Americans). Teslovich et al. (2010) identified several novel loci associated with plasma lipids that are also associated with coronary artery disease. Teslovich et al. (2010) identified rs1367117 in the APOB gene as having an effect on LDL cholesterol with an effect size of +4.05 mg per deciliter and a P value of 4 x 10(-114).
Familial Hypercholesterolemia 2, Autosomal Dominant
Familial hypercholesterolemia-2 (FHCL2; 144010) is caused by mutation in APOB causing decreased LDLR (606945) binding affinity, so-called familial ligand-defective apolipoprotein B. The first mutation of this sort was described by Soria et al. (1989); see 107730.0009. A second was described by Pullinger et al. (1995); see 107730.0017.
Corsini et al. (1989) described familial hypercholesterolemia due not to a defect in the LDLR as in conventional FHCL1 (143890), but to binding-defective LDL, presumably familial defective apoB100. Rajput-Williams et al. (1988) demonstrated association of specific alleles for the apoB gene with obesity, high blood cholesterol levels, and increased risk of coronary artery disease. Several of the RFLPs used as markers do not change the amino acid sequence. The authors concluded that these RFLPs are in linkage disequilibrium with nearby functional variation predisposing to obesity or increased risk of coronary artery disease. Variations in serum cholesterol level were associated with 3 functional alleles corresponding to amino acid variants at positions 3611 and 4154, both of which lie near the LDLR binding region of apoB. Products of the APOB gene with high or low affinity for the MB-19 monoclonal antibody can be distinguished. Gavish et al. (1989) used this antibody to identify heterozygotes and detect allele-specific differences in the amount of APOB in the plasma. A family study confirmed that the unequal expression phenotype was inherited in an autosomal dominant manner and was linked to the APOB locus.
Noting that large-scale genetic cascade screening for familial hypercholesterolemia showed that 15% of LDLR or APOB mutation carriers had LDLC levels below the 75th percentile, Huijgen et al. (2010) proposed 3 criteria for determining pathogenicity of such mutations: mean LDLC greater than the 75th percentile, higher mean LDLC level in untreated than in treated carriers, and higher percentage of medication users in carriers than in noncarriers at screening. Applying these criteria to 46 mutations found in more than 50 untreated adults, 3 of the mutations were determined to be nonpathogenic: 1 in LDLR and 2 in APOB. Nonpathogenicity of the 3 variants was confirmed by segregation analysis. Huijgen et al. (2010) emphasized that novel sequence changes in LDLR and APOB should be interpreted with caution before being incorporated into a cascade screening program.
Familial Hypobetalipoproteinemia
Antonarakis (1987) and his colleagues identified a missense point mutation in the APOB gene associated with hypobetalipoproteinemia (615558). The mutation occurred at a potential site of binding of APOB to LDLR and apparently resulted in interference with the metabolism of apolipoprotein B. The finding of no recombination between the hypobetalipoproteinemia phenotype and a particular DNA haplotype of the APOB gene (Leppert et al., 1988) indicated that, at least in the family studied, hypobetalipoproteinemia was the result of a molecular defect in apolipoprotein B.
As indicated in the listing of allelic variants, a number of mutations resulting in a truncated apolipoprotein B have been found as the basis of hypobetalipoproteinemia. Other patients with this disorder have been found to have reduced concentrations of a full-length apoB100 (Young et al., 1987; Berger et al., 1983; Gavish et al., 1989).
Linton et al. (1993) tabulated 25 apoB gene mutations associated with familial hypobetalipoproteinemia.
Pulai et al. (1998) commented that various truncated forms of apoB have been found to segregate with the FHBL phenotype in more than 30 kindreds.
Schonfeld (1995, 1998) stated that in all reported kindreds in which the 'hypobeta' trait cosegregated with an apoB truncation, heterozygotes (documented by either protein or genomic DNA analysis) showed the trait. In fasting heterozygotes, there are 2 populations of apoB-containing lipoproteins: those that contain the truncation and those that contain the normal full-length apoB100. The low cholesterol levels are due to the low levels of apoB-containing lipoproteins (VLDL and particularly LDL) that transport most of the cholesterol in plasma. In turn, low levels of apoB are due to low production rates of both mutant and wildtype forms of apoB in heterozygotes. In some cases, there is also enhanced clearance from plasma. Low production of a truncated form is probably due to low levels of the truncation-specifying mRNA. It is not clear why wildtype apoB100 is produced at lower than expected rates in heterozygotes. The truncated forms of apoB are named according to a centile nomenclature.
Kairamkonda and Dalzell (2003) described 3 sibs with vitamin E deficiency and symptoms of malabsorption with documented excessive fecal fat excretion and low cholesterol, apoB, and vitamin E levels. Although the pathogenesis was not established, the authors postulated that the sibs had heterozygous FHBL due to a novel mutation of apoB because of persistent posttherapeutic low cholesterol and apoB levels.
Di Leo et al. (2007) identified 3 novel splice site mutations of the APOB gene in 4 FHBL patients and analyzed apoB mRNA in the liver of 1 proband and in transfected COS-1 cells in the other probands. The authors determined that all 3 mutations resulted in truncated apoB proteins that were not secreted as constituents of plasma lipoproteins, confirming the pathogenic effect of rare splice site mutations of the APOB gene found in FHBL.
In a 27-year-old woman from a consanguineous French Canadian family, who was diagnosed with FHBL in the first months of life, Gangloff et al. (2011) identified a homozygous truncating mutation in the APOB gene (107730.0022). The authors stated that this was the first case of homozygous FHBL in a French Canadian family.
Apolipoprotein B Allotypes
Allison and Blumberg (1961) and Blumberg and Riddell (1963) described a polymorphic system including serum beta lipoprotein distinct from that discovered by Berg and Mohr and designated Lp(a) (see 152200). They detected this by the study of patients who had received multiple transfusions. The first type was called Ag-a; the second was called Ag-b. Blumberg et al. (1964) proposed the symbol LP for lipoprotein. Lower case letters are used for designating different loci (i.e., LPa, LPb, LPc, etc.) and superscript numbers for alleles at the locus (i.e., LPa-1, LPa-2, etc.). Retention of the Ag designation may be advisable to avoid confusion with the Berg type. Jackson et al. (1974) observed a family in which variation of a chromosome 21 appeared to be linked with Ag type. The peak lod score was 2.1 at a recombination fraction of 0.0. Berg et al. (1975), on the other hand, found considerable recombination with IPO-A (147450), in family studies. IPO-A is known to be on chromosome 21 from hybrid cell studies. Berg et al. (1976) showed that serum cholesterol and triglyceride levels were higher in Ag(x-) than in Ag(x+) persons. Thus, a small but significant effect of a single autosomal locus in atherogenesis may have been demonstrated. Morganti et al. (1975) indicated that there are at least 5 closely linked loci. This serum protein polymorphism was discovered by Blumberg on the basis of his hypothesis that multitransfused patients should have antibodies against polymorphic serum proteins. The Australia antigen was found in the process of the same studies, applying the additional principle that the wider the anthropologic spread of sera tested (e.g., Australian aborigines), the greater the likelihood of finding a polymorphism. Of course, the Australia antigen proved to be not a polymorphism but a viremia--an even more important discovery, as recognized by the Nobel Prize. By this approach, Blumberg (1978) found other apparent polymorphisms that he has not yet fully studied. Allotypic variation in LDL comparable to Ag has been found in most species studied. Berg et al. (1986) demonstrated close linkage of the Ag allotypes of LDL and DNA polymorphisms at the APOB locus. Linkage disequilibrium (allelic association) was found between the Ag polymorphism and 2 of the 3 DNA polymorphisms studied. Xu et al. (1989) demonstrated that a particular Ag epitope (h/i) is determined by an arginine-to-glutamine substitution at residue 3611 of the mature protein. The amino acid difference results from a CGG-to-CAG change and causes loss of an MspI restriction site. Breguet et al. (1990) found that, with the exception of the Amerindians, the Ag system is highly polymorphic in populations worldwide. They suggested that the system has evolved as a neutral or nearly-neutral polymorphism and is therefore highly informative for 'modern human peopling history' studies. Following the cloning of the human APOB gene, nucleotide substitutions were reported as candidates for the molecular basis of all the Ag epitopes (reviewed by Dunning et al., 1992). Dunning et al. (1992) found complete linkage disequilibrium between the immunochemical polymorphism of LDL that is designated antigen group Ag(x/y) and the alleles at 2 sites in the mature apoB100 molecule: pro2712-to-leu and asn4311-to-ser. It appeared that the Ag(y) epitope was associated with asparagine-4311 plus proline-2712, whereas the allele encoding serine-4311 plus leucine-2712 represented the Ag(x) epitope. In 4 different population groups, they found complete association between the sites encoding residues 2712 and 4311, although there were large allele frequency differences between these populations. In addition, there was strong linkage disequilibrium with allelic association between the alleles of these sites and those of the XbaI RFLP in all populations examined. Taken together, these data suggest that there has been little or no recombination in the 3-prime end of the human APOB gene since the divergence of the major ethnic groups.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Rapacz et al. (1986) described a strain of pigs bearing 3 immunogenetically defined lipoprotein-associated markers (allotypes) associated with marked hypercholesterolemia despite a low-fat, cholesterol-free diet. LDL receptor activity was normal. By 7 months of age the animals had extensive atherosclerotic lesions in all 3 coronary arteries. One of the 3 variant apolipoproteins was apolipoprotein B. The identity of the other 2 apolipoproteins was not clear, although one was a component of low density lipoprotein and was genetically linked to the variant identified with apolipoprotein B.
Homanics et al. (1993) used gene targeting to generate a mouse model of hypobetalipoproteinemia. Mice carrying the disrupted Apob gene synthesized apoB48 and a truncated apoB (apoB70) but no apoB100. In addition to having a lipoprotein phenotype remarkably similar to familial hypobetalipoproteinemia in humans, these mice also exhibited exencephalus and hydrocephalus. Huang et al. (1995) likewise generated APOB gene knockout mice by targeting the gene in embryonic stem cells. Homozygous deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some liveborn heterozygotes developing hydrocephalus. Most heterozygous males were sterile, although the GU system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total LDL and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal APOB mRNA levels were decreased in heterozygotes.
Callow et al. (1995) noted that the engineering of mice that express a human APOB transgene results in animals with high levels of human-like LDL particles. Additionally, through crosses with transgenics for the human LPA gene, high levels of human-like lipoprotein(a) particles are seen. Callow et al. (1995) found that such mice demonstrated marked increases in apoB and LDL, resulting in atherosclerotic lesions extending down the aorta that resembled human lesions immunochemically. The findings suggested to the authors that APO(a) associated with apo(B) and lipid may result in a more pro-atherogenic state than when APO(a) is free in plasma.
Huang et al. (1996) found that male mice heterozygous for targeted mutation of the ApoB gene exhibit severely compromised fertility. Sperm from these mice fail to fertilize eggs both in vitro and in vivo. However, these sperm were able to fertilize eggs once the zona pellucida was removed but displayed persistent abnormal binding to the egg after fertilization. In vitro fertilization-related and other experiments revealed reduced sperm motility, survival time, and sperm count also contributed to the infertility phenotype. Recognition of the infertility phenotype led to the identification of ApoB mRNA in the testes and epididymides of normal mice, and these transcripts were substantially reduced in the mutant animal. Moreover, when the genomic sequence encoding human ApoB was introduced into these animals, normal fertility was restored. The findings of Huang et al. (1996) suggested that APOB may have an important impact on male fertility and identified a previously unrecognized function of ApoB.
To provide models for understanding the physiologic purpose for the 2 forms of apoB (B100 and B48), Farese et al. (1996) used targeted mutagenesis of the APOB gene to generate mice that synthesized apoB48 exclusively and mice that synthesized apoB100 exclusively. The B48-only and B100-only mice were produced by introducing into mouse ES cells stop and nonstop mutations, respectively, in the apoB48 editing codon (codon 2153) of the mouse Apob gene. Both types of mice developed normally, were healthy, and were fertile. Thus, apoB48 synthesis sufficed for normal embryonic development, and the synthesis of apoB100 in the intestine adult mice caused no readily apparent adverse effects on intestinal function or nutrition. Compared with wildtype mice fed the same diet, the levels of LDL cholesterol and VLDL and LPL triacylglycerols were lower in the B48-only mice and higher in the B100-only mice. Farese et al. (1996) stated that in the setting of apo-E deficiency, the B100-only mutation lowered cholesterol levels, consistent with the fact that B100-lipoproteins can be cleared from the plasma via the LDL receptor, whereas B48-lipoproteins lacking apo-E cannot.
Boren et al. (1998) expressed mutant forms of human apoB in transgenic mice, purified the resulting human recombinant LDL, and tested for their receptor-binding activity. They showed that amino acids 3359 to 3369 bind to the LDL receptor and that arginine-3500 is not directly involved in receptor binding. However, the C-terminal 20% of apoB100 is necessary for the R3500Q mutation to disrupt receptor binding, since removal of the C terminus in familial defective apoB100 (FDB) LDL resulted in normal receptor-binding activity. Similarly, removal of the C terminus of apoB100 on receptor-inactive VLDL dramatically increased apoB-mediated receptor-binding activity. Boren et al. (1998) proposed that the C terminus normally functions to inhibit the interaction of apoB100 VLDL with the LDL receptor, but after the conversion of triglyceride-rich VLDL to smaller cholesterol-rich LDL, arginine-3500 interacts with the C terminus, permitting normal interaction between LDL and its receptor. Moreover, the loss of arginine at this site destabilizes this interaction, resulting in receptor-binding defective LDL.
Skalen et al. (2002) created transgenic mice expressing 5 types of human recombinant LDL, fed them an atherogenic diet for 20 weeks, and quantitated the extent of atherosclerosis. They used these models to test the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively-charged sulfate groups on the proteoglycans. Skalen et al. (2002) presented direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wildtype control LDL. Skalen et al. (2002) concluded that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.
In order to demonstrate the therapeutic potential of short interfering RNAs (siRNAs), Soutschek et al. (2004) demonstrated that chemically modified siRNAs can silence an endogenous gene encoding apoB after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB mRNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. Soutschek et al. (2004) also showed that these siRNAs could silence human apoB in a transgenic mouse model. In their in vivo study, the mechanism of action for the siRNAs was proven to occur through RNA interference (RNAi)-mediated mRNA degradation, and Soutschek et al. (2004) determined that cleavage of the apoB mRNA occurred specifically at the predicted site.
Espinosa-Heidmann et al. (2004) studied the development of basal laminar deposits in the eyes of transgenic mice that overexpressed apoB100. The mice were fed a high-fat diet, and their eyes were exposed to blue-green laser light. The results suggested that age and high-fat diet predisposed to the formation of basal laminar deposits by altering hepatic and/or retinal pigment epithelial lipid metabolism in ways more complicated than plasma hyperlipidemia alone. Vitamin E-treated mice showed minimal formation of basal laminar deposits.
In the eyes of transgenic mice overexpressing human apoB100 in the RPE, Fujihara et al. (2009) observed ultrastructural changes consistent with early human age-related macular degeneration (ARMD) (see 603075), including loss of basal infoldings and accumulation of cytoplasmic vacuoles in the RPE and basal laminar deposits containing long-spacing collagen and heterogeneous debris in Bruch membrane. In apoB100 mice given a high-fat diet, basal linear-like deposits were identified in 12-month-old mice. Linear regression analysis showed that the genotype was a stronger influencing factor than high-fat diet in producing ARMD-like lesions.
In a patient with hypobetalipoproteinemia (615558) and small amounts of a truncated apoB protein (B37) in VLDL, LDL, and HDL fractions of the plasma, Young et al. (1987, 1988) found deletion of 4 nucleotides (5391_5394del4) resulting in a frameshift causing change of asn1728 to thr (N1728T) and ser1729 to stop (S1729X). The truncated apoB protein contained 1,728 amino acids. This was one of the mutant alleles in the family with hypobetalipoproteinemia first reported by Steinberg et al. (1979). Linton et al. (1992) investigated the reason for the curious finding that low levels of apoB100 were produced by the mutant allele carrying this mutation. The clue that led to the understanding of what was going on with this allele was the recognition that the proband in the family, H.J.B., as well as the other 2 compound heterozygotes, actually had 4 bona fide apoB species within their plasma lipoproteins: apoB37, apoB48, apoB100, and apoB86. Linton et al. (1992) demonstrated that the apoB86 and apoB100 were products of a single mutant apoB allele, which they designated the apoB86 allele. They showed that this allele has a 1-bp deletion in exon 26 of the APOB gene (107730.0016) and that this frameshift is responsible for the synthesis of apoB86. Nevertheless, as shown by cell culture expression studies, the apoB86 allele, which contains a premature stop codon, results in the synthesis of a full-length apoB protein. The 1-bp deletion creates a stretch of 8 consecutive adenines. Addition of a single adenine within the 8 consecutive adenines appears to take place during transcription, restoring the correct reading frame and accounting for the formation of apoB100 by the apoB86 allele. Eleven percent of the cDNA clones had an additional adenine within the stretch of 8 adenines.
Collins et al. (1988) described a truncated apoB protein due to deletion of a single guanine nucleotide from leucine codon 1794, resulting in a frameshift and a stop codon after codon 1799, as a cause of familial hypobetalipoproteinemia (615558). The truncated protein was referred to as apoB39. The mutation occurred in a CpG dinucleotide.
A second truncated variant of apoB found in familial hypobetalipoproteinemia (615558) by Collins et al. (1988) had a change of arginine codon 1306, converting it to a stop codon and resulting in a protein of 1,305 residues which, however, could not be detected in the circulation. This mutation was a C-to-T transition in a CpG dinucleotide.
Krul et al. (1989) found 2 distinct truncated apoB proteins, apoB40 and apoB90, in a kindred with hypobetalipoproteinemia (615558). Talmud et al. (1989) showed that the molecular basis was deletion of 2 nucleotides converting val1829 to cys and codon 1830 to stop.
See Krul et al. (1989). The molecular basis of familial hypobetalipoproteinemia (615558) was deletion of 1 nucleotide in glutamic acid codon 4034 converting that codon to arginine and causing a frameshift with a stop codon at position 4040 (Talmud et al., 1989). Parhofer et al. (1992) showed that enhanced catabolism of VLDL, IDL, and LDL particles containing the truncated apolipoprotein is responsible for the relatively low levels of apoB89 seen in these subjects.
Young et al. (1989) characterized an apoB gene mutation in a kindred with familial hypobetalipoproteinemia (615558). Six members of the family had low plasma apoB and LDL cholesterol levels, and each was shown to be heterozygous for a mutant apoB allele that yielded a unique truncated species of apoB, namely apoB46, with only 2,037 amino acids. They further showed that apoB46 is caused by the substitution of T for C at apoB cDNA nucleotide 6381, resulting in a nonsense mutation. The change occurred in a CG dinucleotide. A C-to-T transition in the APOB gene was responsible for hypobetalipoproteinemia in one of the families studied by Collins et al. (1988). Like CETP deficiency (143470), this appears to be an antiatherogenic mutation.
In a family segregating hypobetalipoproteinemia (615558), Gabelli et al. (1996) identified 2 sibs who were homozygous for a 1-bp deletion in the APOB gene (12032delG), causing a frameshift and termination at amino acid 3978. The truncated apoB form was designated apoB-87-Padova. Although the 2 homozygous members had only trace amounts of low density lipoprotein, they were virtually free from symptoms typical of homozygous FHBL subjects. Seven members of the family who were heterozygous for the mutation were asymptomatic, with LDL cholesterol concentrations corresponding to about 50% of normal values.
Young et al. (1990) identified a mutation of the APOB gene that resulted in formation of a truncated apoB species, apoB31, as a cause of familial hypobetalipoproteinemia. The mutation consisted of deletion of a single guanine residue which caused a frameshift and a premature termination with formation of a protein predicted to contain 1,425 amino acids. This is the shortest of the mutant apoB species identified in the plasma of subjects with hypobetalipoproteinemia. In contrast to the longer truncated proteins, apoB31 was undetectable in VLDL and LDL but was present in the HDL fraction and in the lipoprotein-deficient fraction of the plasma. This mutation was found in the course of studying the apoB46 mutant (Young et al., 1989).
By extensive sequence analysis of the 2 alleles of the APOB gene in a man with moderate hypercholesterolemia (FHCL2; 144010), who was originally reported by Vega and Grundy (1986) and was found to be heterozygous for familial defective apolipoprotein by Innerarity et al. (1987), Soria et al. (1989) demonstrated a mutation in the codon for amino acid 3500 that results in the substitution of glutamine for arginine. This same mutant allele was found in 6 other, unrelated subjects and in 8 affected relatives in 2 of these families. A partial haplotype of this mutant apoB100 allele was constructed by sequence analysis and restriction enzyme digestion at positions where variations in the apoB100 are known to occur. This haplotype was found to be the same in 3 probands and 4 affected members of 1 family and lacks a polymorphic XbaI site whose presence has been correlated with high cholesterol levels. Thus, it appears that the mutation in the codon for amino acid 3500 (CGG-to-CAG), a CG mutation hotspot, defines a minor apoB100 allele associated with defective low density lipoproteins and hypercholesterolemia.
Ludwig and McCarthy (1990) used 10 markers for haplotyping at the APOB locus in cases of familial defective apolipoprotein B100: 8 diallelic markers within the structural gene and 2 hypervariable markers flanking the gene. In 14 unrelated subjects heterozygous for the mutation, 7 of 8 unequivocally deduced haplotypes were identical, and 1 revealed only a minor difference at one of the hypervariable loci. The genotypes of the other 6 affected subjects was consistent with the same haplotype. Familial defective apolipoprotein B100 (FDB) results from a G-to-A transition at nucleotide 10708 in exon 26 of the APOB gene. Ludwig and McCarthy (1990) interpreted the data as consistent with the existence of a common ancestral chromosome.
In a screening for the APOB3500 mutation by PCR amplification and hybridization with an allele-specific oligonucleotide, Loux et al. (1993) found only 1 case among 101 French subjects with familial hypercholesterolemia. The son of this individual, a 45-year-old man, was found also to have the mutation. Haplotype analysis revealed strict identity to that previously reported by Ludwig and McCarthy (1990), thus supporting a unique European ancestry. The family lived in the southwest of France and had no knowledge of Germanic origin.
Rauh et al. (1992) stated that the frequency of the arg3500-to-gln mutation has been found to be approximately 1/500 to 1/700 in several Caucasian populations in North America and Europe. On the other hand, Friedlander et al. (1993) found no instance of this mutation in a large screening program in Israel. They pointed out that the mutation has also not been found in Finland (Hamalainen et al., 1990) and is said to be absent in Japan. Tybjaerg-Hansen and Humphries (1992) gave a review suggesting that the risk of premature coronary artery disease in the carriers of the mutation is increased to levels as high as those seen in patients with familial hypercholesterolemia; at age 50, about 40% of males and 20% of females heterozygous for the mutation have developed coronary artery disease.
Marz et al. (1992) found only moderate hypercholesterolemia in a 54-year-old man who was homozygous for the arg3500-to-gln mutation and on a normal diet without lipid-lowering medication. There was no evidence of atherosclerosis and no history of cardiovascular complaints. The levels of apoE-containing lipoproteins were normal. Marz et al. (1992) suggested that the intact metabolism of apoE-containing particles decreases LDL production in this disorder, explaining the difference from familial hypercholesterolemia due to a receptor defect in which apoE levels are raised. Marz et al. (1993) investigated possible compensatory mechanisms that may have alleviated the consequences of the familial defective apoB100 (FDB). They showed that the receptor interaction of buoyant LDL is normal due to the presence of apoE in these particles. In addition, they provided evidence that the arg3500-to-gln substitution profoundly alters the conformation of the apoB receptor binding domain when apolipoprotein B resides on particles at the lower and upper limits of the LDL density range. They concluded that these mechanisms distinguish FDB from FH and account for the mild hypercholesterolemia in homozygous FDB. Among 43 patients with clinically and biochemically defined type III hyperlipoproteinemia (107741), Feussner and Schuster (1992) found no instance of the arg3500-to-gln mutation.
In the course of investigating 2 unrelated French patients heterozygous for mutations in the LDLR gene (606945) who had aggravated hypercholesterolemia, Benlian et al. (1996) found that each carried the identical arg3500-to-gln mutation in the APOB gene, i.e., were double heterozygotes. One of the patients was a 10-year-old boy when he was referred for hypercholesterolemia discovered at the time of a cardiac arrest. He had no planar xanthomata, although he exhibited bilateral xanthomas of the Achilles and metacarpal phalangeal tendons. Peripheral arterial disease was demonstrated by the presence of arterial murmurs and by arterial wall irregularity on ultrasound analysis. Stenoses of coronary arteries necessitated surgical angioplasty. The second patient was a 39-year-old man with myocardial infarction and acute ischemia of the legs. Both families came from the Perche region from which many French Canadians originated. The LDLR mutations trp66-to-gly (606945.0003) and glu207-to-lys (606945.0007) had previously been described in French Canadians. Rubinsztein et al. (1993) described an Afrikaner family with 6 FH/FDB double heterozygotes carrying another LDLR mutation, asp206-to-glu (606945.0006). (Benlian et al. (1996), in the title of their article, correctly referred to these patients as double heterozygotes; in the paper itself they incorrectly referred to them as FH/FDB compound heterozygotes. The latter term is used for heterozygosity for alleles at the same locus.)
In a patient homozygous for the R3500Q mutation, Schaefer et al. (1997) found LDL cholesterol and apoB concentrations approximately twice normal, whereas apoE plasma level was low. Using a stable-isotope labeling technique, they obtained data showing that the in vivo metabolism of apoB100-containing lipoproteins in FDB is different from that in familial hypercholesterolemia, in which LDL receptors are defective. Although the residence times of LDL apoB100 appeared to be increased to approximately the same degree, LDL apoB100 synthetic rate was increased in FH and decreased in FDB. The decreased production of LDL apoB100 in FDB may originate from enhanced removal of apoE-containing LDL precursors by LDL receptors, which may be upregulated in response to the decreased flux of LDL-derived cholesterol into hepatocytes.
Almost all individuals with familial defective apoB100 are of European descent, and in almost all cases the mutation is on a chromosome with a rare haplotype at the apoB locus, suggesting that all probands are descended from a common ancestor in whom the original mutation occurred. Distribution of the mutation is consistent with an origin in Europe 6,000 to 7,000 years ago. Myant et al. (1997) estimated the amount of recombination between the APOB gene and markers on chromosome 2 in 34 FDB (R3500Q) probands in whom the mutation is on the usual 194 haplotype. Significant linkage disequilibrium was found between the APOB gene and marker D2S220. They identified 3 YACs that contained the APOB gene and D2S220. The shortest restriction fragment common to the 3 YACs that contain both loci was 240 kb long. No shorter fragments with both loci were identified. On the assumption that 1000 kb corresponds to 1 cM, Myant et al. (1997) deduced that the recombination distance between D2S220 and the APOB gene is about 0.24 cM. Combining this value with the linkage disequilibrium observed between the 2 loci in the probands, they estimated that the ancestral mutation occurred about 270 generations ago. They postulated that the original mutation occurred in the common ancestor of living FDB (R3500Q) probands, who lived in Europe about 6,750 years ago.
Tybjaerg-Hansen et al. (1998) found that the R3500Q mutation in the APOB gene is present in approximately 1 in 1,000 persons in Denmark and causes severe hypercholesterolemia and increases the risk of ischemic heart disease. Heterozygous carriers of the arg3531-to-cys (107730.0017) mutation, which is present in the population in approximately the same frequency and also is associated with familial defective apolipoprotein B100, was not associated with higher-than-normal plasma cholesterol levels or an increased risk of ischemic heart disease.
Saint-Jore et al. (2000) estimated the respective contributions of the LDLR gene defect, APOB gene defect, and other gene defects in autosomal dominant type IIa hypercholesterolemia by studying 33 well-characterized French families in which this disorder had been diagnosed over at least 3 generations. Using the candidate gene approach, they found that defects in the LDLR gene accounted for the disorder in about 50% of the families. The estimated contribution of an APOB gene defect was only 15%. This low estimation of involvement of the APOB gene defect was strengthened by the existence of only 2 probands carrying the R3500Q mutation. Surprisingly, 35% of the families were estimated to be linked to neither LDLR nor APOB. The results suggested that genetic heterogeneity in type IIa hypercholesterolemia had been underestimated and that at least 3 major groups of defects were involved. The authors were unable to estimate the contribution of the FH3 gene (603776).
Boren et al. (2001) concluded that normal receptor binding of LDL involves an interaction between arginine-3500 and tryptophan-4369 in the carboxyl tail of apoB100. Trp4369 to tyr (W4369Y) LDL and arg3500 to gln (R3500Q) LDL isolated from transgenic mice had identically defective LDL binding and a higher affinity for a monoclonal antibody that has an epitope flanking residue 3500. Boren et al. (2001) concluded that arginine-3500 interacts with tryptophan-4369 and facilitates the conformation of apoB100 required for normal receptor binding of LDL. They developed a model that explained how the carboxyl terminus of apoB100 interacts with the backbone of apoB100 that enwraps the LDL particle. The model explained how all known ligand-defective mutations in apoB100, including a newly discovered R3480W mutation, cause defective receptor binding.
Horvath et al. (2001) studied 130 unrelated individuals with hypercholesterolemia in Bulgaria. Four of these individuals were found to be carriers of this mutation. Horvath et al. (2001) concluded that this mutation accounts for 0.99 to 8.17% (95% CI) of cases of hypercholesterolemia in Bulgaria and therefore represents the most common single mutation associated with this condition in Bulgaria.
Bednarska-Makaruk et al. (2001) found the arg3500-to-gln mutation in 2.5% (13/525) of unrelated patients with hypercholesterolemia in Poland. All the patients belonged to the type IIA hyperlipoproteinemia group. In 65 patients with the clinical characteristics of familial hypercholesterolemia, the frequency of the arg3500-to-gln mutation was 10.8% (7/65). The same haplotype at the APOB locus in the carriers of this mutation in Poland as in other populations from western Europe suggested its common origin.
In an Arab patient with hypobetalipoproteinemia and absent plasma apolipoprotein B (615558), Huang et al. (1989) demonstrated deletion of the entire exon 21 (211 basepairs coding for amino acids 1014 to 1084).
Visvikis et al. (1990) described an insertion/deletion polymorphism in the signal peptide. One allele, coding a peptide 27 amino acids long, had a frequency of 0.655; the second allele, coding a peptide 24 amino acids long, had a frequency of 0.345.
In a man and 6 of his children with hypobetalipoproteinemia (615558), Welty et al. (1991) found that the plasma lipoproteins contained a unique species of apolipoprotein B, apoB67, in addition to the normal species, apoB100 and apoB48. Further study indicated that the apoB67 was a truncated species that contained approximately the amino-terminal 3,000 to 3,100 amino acids of apoB100. Heterozygosity was identified for a mutant APOB allele containing a single nucleotide deletion in exon 26 (cDNA nucleotide 9327). The change in codon 3041 from ATA (leu) to TAG (stop) led to truncation after amino acid 3040. Mean total and LDL cholesterol levels were 120 and 42 mg/dl, respectively. All affected members of the kindred had high HDL cholesterol levels.
Malloy et al. (1981) described a patient (A.F.) with a metabolic disorder that they termed normotriglyceridemic abetalipoproteinemia (615558). Similar cases were reported by Takashima et al. (1985), Herbert et al. (1985), and Harano et al. (1989). The disorder was characterized by the absence of LDLs and apoB100 in plasma with apparently normal secretion of triglyceride-rich lipoproteins containing apoB48. Subsequent studies in A.F. suggested that the patient's plasma might be a truncated form of apoB100, slightly longer than the normal apoB48 chain. Hardman et al. (1991) demonstrated that the patient was homozygous for a single C-to-T substitution at nucleotide 6963 of apoB cDNA. This substitution resulted in a change from CAG (glutamine) to TAG (stop) at position 2252. Thus, this was a rare example of homozygous hypobetalipoproteinemia. Because LDL particles that contained apoB50 lacked the putative ligand domain of the LDL receptor, the very low level of LDL was presumably due to the rapid removal of the abnormal VLDL particles before their conversion to LDL could take place. As reviewed by Hardman et al. (1991), a considerable number of mutations resulting in truncated versions of apoB have been described, the smallest variant being apoB31, and the longest, apoB90. Using 3 genetic markers of the APOB gene in a study of the family reported by Takashima et al. (1985), Naganawa et al. (1992) found that the proband and her affected brother showed completely different APOB alleles, indicating that in this family the defect was not in the APOB gene.
Homer et al. (2005) suggested that the term 'normotriglyceridemic hypobetalipoproteinemia' is preferred to 'normotriglyceridemic abetalipoproteinemia' because abetalipoproteinemia (ABL; 200100) refers to the disorder caused by mutation in the MTP gene (157147).
In a person with heterozygous hypobetalipoproteinemia (615558), McCormick et al. (1992) identified a nonsense mutation, gln1450-to-ter (Q1450X), that prevented full-length translation. The new apolipoprotein B, apoB32, is predicted to contain the 1,449 N-terminal amino acids of apoB100. It was associated with a markedly decreased level of low density lipoprotein (LDL cholesterol). Unique among the truncated apoB species, apoB32 was found in the high density lipoprotein and lipoprotein-depleted fractions, suggesting that it was mainly assembled into abnormally dense lipoprotein particles.
In a patient with familial hypobetalipoproteinemia (615558), Talmud et al. (1992) identified a C-to-T transition at nucleotide 7692 of the APOB gene which changed the CGA arginine codon to a stop codon resulting in a premature termination of apoB100. The truncated protein was predicted to be 2,494 amino acids long with the predicted size of apoB55. The patient had low total cholesterol and LDL-cholesterol as did also other relatives in an autosomal dominant pattern. In addition, the propositus, his mother, and both of his sibs had atypical retinitis pigmentosa. Since the RP-affected brother did not have the APOB mutation, Talmud et al. (1992) concluded that the eye disease was independent of the hypobetalipoproteinemia. They speculated, however, that a reduction in apoB-containing lipoproteins might alter the balance of the fatty acid supply to the retina and thus affect the evolution of retinitis pigmentosa in this family. The retinitis pigmentosa was late in onset.
In H.J.B. and 2 sibs with asymptomatic familial hypobetalipoproteinemia (615558) reported by Steinberg et al. (1979), Linton et al. (1992) demonstrated that one of the alleles, which yielded very low levels of apoB100, had a deletion of a single cytosine in exon 26 (nucleotide 11840 of the apoB cDNA). This frameshift mutation was predicted to yield a 20-amino acid sequence (KKQIMLKQSWIPHAAQPYSS) not found in the wildtype, followed by a premature stop codon. Indeed, they found an antiserum to a synthetic peptide containing this 20-amino acid sequence (frameshift peptide 3877-3896) bound specifically to apoB86 but not to apoB100. Thus the compound heterozygotes had 2 mutant apoB alleles, one primarily responsible for apoB37 (107730.0001) and the other responsible for apoB86, both of which contained frameshift mutations in exon 26. Linton et al. (1992) further demonstrated that the 1-bp deletion in the apoB86 allele created a stretch of 8 consecutive adenines. Addition of a single adenine within the 8 consecutive adenines would be predicted to correct the altered reading frame, thereby resulting in the production of a full-length protein. They presented evidence that a significant percentage (about 11%) of the apoB cDNA clones from rat hepatoma cells transformed with an apoB construct containing the 1-bp deletion indeed had 9 consecutive adenines. It appeared that the addition of an extra adenine during transcription restored the correct reading frame and accounted for the formation of some apoB100 from the apoB86 allele. Other experiments were thought to exclude an alternative explanation, the activation of a cryptic splice site within exon 26 upstream from the deletion.
Suspecting that mutations in the APOB gene other than the arg3500-to-gln mutation (107730.0009) may cause familial hypercholesterolemia (FHCL2; 144010), Pullinger et al. (1995) used single-strand conformation polymorphism analysis to screen genomic DNA from patients attending a lipid clinic and looked for mutations in the putative LDL receptor-binding domain of apoB100. They found a novel arg3531-to-cys mutation, caused by a C-to-T transition at nucleotide 10800, in a 46-year-old woman of Celtic and Native American ancestry with primary hypercholesterolemia and pronounced peripheral vascular disease. After screening 1,560 individuals, one unrelated 59-year-old man of Italian ancestry was found to have the same mutation. He had coronary heart disease, a triglyceride cholesterol of 310 mg/dl, and an LDL cholesterol of 212 mg/dl. A total of 8 individuals were found with the same defect in the families of these 2 patients. The age- and sex-adjusted TC and LDL-C were 240 and 169, respectively, for the 8 affected individuals, as compared with 185 and 124, respectively, for 8 unaffected family members. In a dual-labeled fibroblast binding assay, LDL from the 8 subjects with the mutation had an affinity for the LDL receptor that was 63% of that of control LDL. LDL from 8 unaffected family members had an affinity of 91%. By way of comparison, LDL from 6 patients heterozygous for the arg3500-to-gln mutation had an affinity of 36%. Deduced haplotypes using 10 APOB gene markers showed the arg3531-to-cys alleles to be different in the 2 kindreds and indicated that the mutations arose independently. This was the second reported cause of familial ligand-defective apoB.
Hegele and Miskie (2002) described acanthocytosis in a 31-year-old woman with homozygous familial hypobetalipoproteinemia (615558) due to a splicing mutation in the APOB gene, IVS7-2A-G. Treatment with fat-soluble vitamins was associated with arrest of the usually progressive neurologic complications of this condition. However, acanthocytosis persisted. The diagnosis of hypobetalipoproteinemia was made at the age of 11 years on the basis of acanthocytosis and the absence of apoB-containing lipoproteins. The consanguineous parents were heterozygotes.
In a family segregating familial hypobetalipoproteinemia (615558), Yue et al. (2002) described a 1-bp deletion, 4432delT, in exon 26 of the APOB gene, producing a frameshift and a premature stop codon and resulting in a truncated apoB-30.9. Although this truncation was only 10 amino acids shorter than the well-documented apoB31 (107730.0008), which is readily detectable in plasma, apoB-30.9 was undetectable. Most truncations shorter than apoB-30 are not detectable in plasma.
In a patient with normotriglyceridemic hypobetalipoproteinemia (615558), obesity, and mental retardation, Homer et al. (2005) identified compound heterozygosity for 2 mutations in the APOB gene. One was a 4-bp deletion beginning at nucleotide 36491 in exon 26, predicted to result in a frameshift and incorporation of 5 new amino acids before encountering a premature termination codon at position 3053. This translated protein would be 66% of full-length apoB, which would allow for expression in the liver and for production of minute amounts of VLDL and LDL. Accordingly, the patient did not have failure to thrive or steatorrhea. The second mutation was a 29142T-A transversion in exon 23, resulting in a tyr1173-to-ter (Y1173X; 107730.0021) substitution. The translated Y1173X protein is predicted to be 25.8% of apoB100 and is not expressed in apoB-containing lipoproteins. Homer et al. (2005) suggested that the clinical features of ataxia, visual impairment, and probable neuropathy seen in the patient resulted from the inability to transport the active stereoisomer of vitamin E from the liver. These clinical features were similar to those seen in isolated vitamin E deficiency (VED; 277460). Homer et al. (2005) noted that the clinical features of this patient were similar to those of the patient reported by Malloy et al. (1981) (see 107730.0013).
Homer et al. (2005) suggested that the term 'normotriglyceridemic hypobetalipoproteinemia' is preferred to 'normotriglyceridemic abetalipoproteinemia' because abetalipoproteinemia (ABL; 200100) refers to the disorder caused by mutation in the MTP gene (157147).
For discussion of the tyr1173-to-ter (Y1173X) mutation in the APOB gene that was found in compound heterozygous state in a patient with normotriglyceridemic hypobetalipoproteinemia (615558) by Homer et al. (2005), see 107730.0020.
In a 27-year-old woman from a consanguineous French Canadian family, who was diagnosed with familial hypobetalipoproteinemia (FHBL; 615558) in the first months of life, Gangloff et al. (2011) identified a 2-bp insertion (825insGG) in exon 9 of the APOB gene, causing a frameshift predicted to result in a truncated protein that is approximately 7% of the normal APOB length. The proband and 2 younger brothers, aged 12 and 4 years, had undetectable apoB levels, extremely low levels of cholesterol in all lipoprotein fractions, low levels of lipophilic vitamins, and acanthocytosis. Vitamin E deficiency was present in all 3. The obligate-heterozygote parents had plasma levels of apoB-containing lipoproteins that were approximately 50% of normal, suggesting a codominant pattern of inheritance. The parents declined genetic testing for themselves and their younger children.
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