Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: APOA1
SNOMEDCT: 238095002, 66451004;
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:116,835,751-116,837,950 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Amyloidosis, 3 or more types | 105200 | Autosomal dominant | 3 |
| Hypoalphalipoproteinemia, primary, 2 | 618463 | Autosomal recessive | 3 | |
| Hypoalphalipoproteinemia, primary, 2, intermediate | 619836 | Autosomal dominant | 3 |
APOA1 is the major protein component of high density lipoprotein (HDL) in plasma and is primarily synthesized in liver and small intestine (summary by Halley et al., 2014).
Breslow et al. (1982) isolated and characterized cDNA clones for human apoA-I. Apolipoprotein A-I is the major apoprotein of HDL and is a relatively abundant plasma protein with a concentration of 1.0-1.5 mg/ml. It is a single polypeptide chain with 243 amino acid residues of known primary amino acid sequence (Brewer et al., 1978).
ApoA-I is a cofactor for LCAT (606967), which is responsible for the formation of most cholesteryl esters in plasma. ApoA-I also promotes efflux of cholesterol from cells. The liver and small intestine are the sites of synthesis of apoA-I. The primary translation product of the APOA1 gene contains both a pre and a pro segment, and posttranslational processing of apoA-I may be involved in the formation of the functional plasma apoA-I isoproteins. The primary gene transcript encodes a preproapoA-I containing 24 amino acids on the amino terminus of the mature plasma apoA-I (Law et al., 1983). Dayhoff (1976) pointed to sequence homologies of A-I, A-II (107670), C-I (107710), and C-III (107720).
Yui et al. (1988) found that apoA-I is identical to serum PGI(2) stabilizing factor (PSF). They noted that PGI(2), or prostacyclin, is synthesized by the vascular endothelium and smooth muscle, and functions as a potent vasodilator and inhibitor of platelet aggregation. They suggested that the stabilization of PGI(2) by HDL and apoA-I may be an important protective action against the accumulation of platelet thrombi at sites of vascular damage. The beneficial effects of HDL in the prevention of coronary artery disease may be partly explained by this effect.
Martinez et al. (2003) identified a high affinity HDL receptor for apolipoprotein A1 as the beta chain of ATP synthase (ATP5B; 102910), a principal protein complex of the mitochondrial inner membrane. They used a variety of experimental approaches to confirm this ectopic localization of components of the ATP synthase complex and the presence of ATP hydrolase activity at the hepatocyte cell surface. Receptor stimulation by apoA-I triggers the endocytosis of holo-HDL particles (protein plus lipid) by a mechanism that depends strictly on the generation of ADP. Martinez et al. (2003) confirmed this effect on endocytosis in perfused rat liver ex vivo by using a specific inhibitor of ATP synthase. Thus, Martinez et al. (2003) concluded that membrane-bound ATP synthase has a previously unsuspected role in modulating the concentrations of extracellular ADP and is regulated by a principal plasma apolipoprotein.
Zhang et al. (2003) injected (3)H-cholesterol-labeled macrophage foam cells intraperitoneally into mice overexpressing Apoa1 and control mice and detected (3)H-cholesterol in plasma, lung, spleen, liver, and feces. Mice overexpressing Apoa1 had significantly higher plasma (3)H-cholesterol and higher (3)H-tracer in the liver and excreted 63% more (3)H-tracer into feces over 48 hours than did control mice (p less than 0.05). Zhang et al. (2003) concluded that APOA1 overexpression promotes macrophage-specific reverse cholesterol transport.
Halley et al. (2014) identified APOA1AS as an antisense long noncoding RNA (lncRNA) of the APOA1 gene. Knockdown of APOA1AS via short interfering RNA in HepG2 cells resulted in increased expression of APOA1 and its neighboring genes APOC3 and APOA4 (107690) in the APO gene cluster on chromosome 11. Chromatin immunoprecipitation analysis of an approximately 50-kb chromatin region flanking the APOA1 gene demonstrated that APOA1AS modulated distinct histone methylation patterns that marked active and/or inactive gene expression by recruitment of histone-modifying enzymes. Downregulation of APOA1AS via short antisense oligonucleotides led to increased APOA1 expression in both human and monkey liver cells.
Law et al. (1984) assigned the APOA1 gene to 11p11-q13 by filter hybridization analysis of human-mouse cell hybrid DNAs. The genes for apoA-I and apoC-III are on chromosome 9 in the mouse. Mouse homologs of other genes on human 11p (insulin, beta-globin, LDHA, HRAS) are situated on mouse chromosome 7. Using a cDNA probe to detect apoA-I structural gene sequences in human-Chinese hamster cell hybrids, Cheung et al. (1984) assigned the gene to the region 11q13-qter. Since other information had suggested 11p11-q13 as the location, the SRO becomes 11q13. It is noteworthy that in the mouse and in man, APOA1 and PGBD (called Ups in the mouse) are syntenic. Both are on chromosome 11 in man and chromosome 9 in the mouse. Bruns et al. (1984) localized the genes for apoA-I and apoC-III (previously shown to be in a 3-kb segment of the genome; Breslow et al., 1982; Shoulders et al., 1983) to chromosome 11 by Southern blot analysis of DNA from human-rodent cell hybrids. Because in the mouse apoA-I is on chromosome 9 and apoA-II is on chromosome 1 (Lusis et al., 1983), the gene for human apoA-II is probably not on chromosome 11. Indeed, APOA2 (107670) is on human chromosome 1. On the basis of data provided by Pearson (1987), the APOA1 locus was assigned to 11q23-qter by HGM9. This would place APOC3 and APOA4 in the same region. Because the XmnI genotype at the APOA1 locus was heterozygous in a boy with partial deletion of the long arm of chromosome 11, del(11)(q23.3-qter), Arinami et al. (1990) localized the gene to 11q23 by excluding the region 11q24-qter.
Haddad et al. (1986) found that in the rat, as in man, the APOA1, APOC3 and APOA4 genes are closely linked. Indeed, their direction of transcription, size, relative location and intron-exon organization were found to be remarkably similar to those of the corresponding human genes.
The APOA1 and APOC3 genes are oriented 'foot-to-foot,' i.e., the 3-prime end of APOA1 is followed after an interval of about 2.5 kb by the 3-prime end of APOC3 (Karathanasis et al., 1983).
Hypoalphalipoproteinemia, Primary, 2
Many variants in the APOA1 gene have been identified, some of which have been associated with hypoalphalipoproteinemia leading to atherosclerosis, xanthoma, and corneal opacity (see 618463). Mutations that result in undetectable levels of apoA-I in serum and in markedly low levels of serum high density lipoprotein cholesterol (HDL-C) are more likely to result in severe manifestations. In general, individuals with half-normal levels of apoA-I and HDL-C do not have increased cardiovascular risk (summary by Rader and deGoma, 2012).
Lack of detectable plasma apolipoprotein A-I can be due to DNA deletions, rearrangements, or nonsense or frameshift mutations within the APOA1 gene resulting in a lack of apoA-I secretion (summary by Schaefer et al., 2010).
To determine the frequency of de novo hypoalphalipoproteinemia in the general population due to mutation in the APOA1 gene, Yamakawa-Kobayashi et al. (1999) analyzed sequence variations in the APOA1 gene in 67 children with a low high-density lipoprotein cholesterol level. These children were selected from 1,254 school children through a school survey. Four different mutations with deleterious potential, 3 frameshifts and 1 splice site mutation, were identified in 4 subjects. The plasma apoA-I levels of the 4 children with these mutations were reduced to approximately half of the normal levels and were below the first percentile of the general population distribution (80 mg/dl). The frequency of hypoalphalipoproteinemia due to a mutant APOA1 gene was estimated at 6% in subjects with low HDL cholesterol levels and 0.3% in the Japanese population generally.
In an otherwise healthy 42-year-old man with massive corneal clouding, Funke et al. (1991) identified a homozygous 1-bp deletion in the APOA1 gene (107680.0014) as the basic defect responsible for complete absence of HDL from the plasma and corneal opacities. Heterozygous carriers of the deletion, including the proband's mother and 3 of this children, showed approximately half-normal HDL cholesterol concentrations.
In the Japanese woman with apoA-I deficiency, xanthomas, and premature atherosclerosis reported by Hiasa et al. (1986), Matsunaga et al. (1991) identified homozygosity for a nonsense mutation in the APOA1 gene (Q84X; 107680.0015).
In a Sicilian woman, born to first-cousin parents, who developed bilateral periorbital xanthelasmas during her first pregnancy at age 22, Romling et al. (1994) identified homozygosity for a nonsense mutation (Q32X; 107680.0019) in the APOA1 gene. The xanthelasmas did not progress after delivery.
Hypoalphalipoproteinemia, Primary, 2, Intermediate
In 3 healthy Japanese individuals, including a 10-year-old proband and her 34-year-old mother and 36-year-old maternal aunt, with low levels of apoA-I and HDL-C levels, Nakata et al. (1993) identified a heterozygous mutation in the APOA1 gene (107680.0018).
Combined ApoA-I and ApoC-III Deficiency
Rees et al. (1983) studied the cloned APOA1 gene and a DNA polymorphism 3-prime to it. Rees et al. (1985) found a strong correlation between hypertriglyceridemia and a DNA sequence polymorphism located in or near the 3-prime noncoding region of APOC3 and revealed by digestion of human DNA with the restriction enzyme Sst-1 and hybridization with an APOA1 cDNA probe. In 74 hypertriglyceridemic Caucasians, 3 were homozygous and 23 were heterozygous for the polymorphism, giving a gene frequency of 0.19; none of 52 normotriglyceridemics had the polymorphism, although it was frequent in Africans, Chinese, Japanese, and Asian Indians. No differences in high density lipoprotein or in apolipoproteins A-I and C-III phenotypes were found in persons with or without the polymorphism.
Ferns et al. (1985) found an uncommon allelic variant (called S2) of the apoA-I/C-III gene cluster in 10 of 48 postmyocardial infarction patients (21%). In 47 control subjects it was present in only 2 and in none of those who were normotriglyceridemic. (The S2 allele, a DNA polymorphism, is characterized by SstI restriction fragments of 5.7 and 3.2 kb, whereas the common S1 allele produces fragments of 5.7 and 4.2 kb.) Ferns et al. (1985) found no difference in the distribution of alleles in the highly polymorphic region of 11p near the insulin gene.
In Japanese, Rees et al. (1986) found association of triglyceridemia with a different haplotype of the A-I/C-III region than that found in Caucasians.
Ferns et al. (1986) found a common allele of the APOA2 locus which showed a weak association with hypertriglyceridemia; in contrast, an uncommon allele of the APOA1-APOC3-APOA4 gene cluster demonstrated a stronger relationship with hypertriglyceridemia. Ferns et al. (1986) found higher levels of serum triglycerides with possession of both disease-related alleles than with either singly.
In certain patients with premature atherosclerosis, Karathanasis et al. (1987) demonstrated a DNA inversion containing portions of the 3-prime ends of the APOA1 and APOC3 genes, including the DNA region between these genes. The breakpoints of this DNA inversion were found to be located between the fourth exon of the APOA1 gene and the first intron of the APOC3 gene; thus, the inversion results in reciprocal fusion of the 2 gene transcriptional units. The absence of transcripts with correct mRNA sequences causes deficiency of both apolipoproteins in the plasma of these patients, leading to atherosclerosis.
In addition to its ability to remove cholesterol from cells, HDL also delivers cholesterol to cells through a poorly defined process in which cholesteryl esters are selectively transferred from HDL particles into the cell without the uptake and degradation of the lipoprotein particle. In steroidogenic cells of rodents, the selective uptake pathway accounts for 90% or more of the cholesterol destined for steroid production or cholesteryl ester accumulation. To test the importance of the 3 major HDL proteins in determining cholesteryl ester accumulation in steroidogenic cells of the adrenal gland, ovary, and testis, Plump et al. (1996) used mice which had been rendered deficient in apoA-I, apoA-II, or apoE by gene targeting in embryonic stem cells. ApoE and apoA-II deficiencies were found to have only modest effects on cholesteryl ester accumulation. In contrast, apoA-I deficiency caused an almost complete failure to accumulate cholesteryl ester in steroidogenic cells. Plump et al. (1996) interpreted these results as indicating that apoA-I is essential for the selective uptake of HDL cholesteryl esters. They stated that the lack of apoA-I has a major impact on adrenal gland physiology, causing diminished basal corticosteroid production, a blunted steroidogenic response to stress, and increased expression of compensatory pathways to provide cholesterol substrate for steroid production.
Combined ApoA-I/C-III/A-IV Deficiency
Schaefer et al. (1982) studied the plasma lipids of a middle-aged woman who died following coronary artery bypass grafting for atherosclerotic narrowing of multiple arteries. She had markedly reduced high density lipoprotein, no detectable apolipoprotein A-I, normal A-II, and moderately reduced apolipoproteins B and C. Both of her children, all 6 of her living sibs, and both parents had reduced apolipoprotein A-I and HDL levels and normal apolipoprotein A-II. Three of the sibs and their mother had coronary disease. The proband had corneal clouding due to diffuse lipid deposits in the epithelial cells; none of the heterozygotes had this finding. Ordavas et al. (1989) demonstrated that all of the APOA1/APOC3/APOA4 gene complex was deleted from a point about 3.1 kb 5-prime to the APOA1 gene to a point 3-prime to the APOA4 gene.
Familial Combined Hyperlipidemia
Hayden et al. (1987) found an association between certain RFLPs and familial combined hyperlipidemia (FCHL; 144250). In studies of 3 restriction enzyme polymorphisms in the AI-CIII-AIV gene cluster, Dallinga-Thie et al. (1997) analyzed haplotypes and showed an association with severe hyperlipidemia in subjects with FCHL. Furthermore, nonparametric sib pair linkage analysis revealed significant linkage between these markers in the gene cluster and the FCHL phenotype. The findings confirmed that the AI-CIII-AIV gene cluster contributes to the FCHL phenotype, but this contribution is genetically complex. An epistatic interaction between different haplotypes of the gene cluster was demonstrated. They concluded that 2 different susceptibility loci exist in the gene cluster.
Amyloidosis
Genschel et al. (1998) counted 4 naturally occurring mutant forms of apoA-I that were known at that time to result in amyloidosis (see 105200). The most important feature of all variants was the very similar formation of N-terminal fragments found in the amyloid deposits. They summarized the specific features of all known amyloidogenic variants of APOA1 and speculated about the metabolic pathway involved.
Schaefer et al. (2016) reviewed apoA-I-derived amyloidosis. The majority of the amyloidogenic mutations are located in 2 hotspot regions in that span amino acid residues 26-107 and 154-178. The mutations result in the formation of apoA-I-amyloid protein complexes. This causes enhanced amyloid proteolysis and amyloid deposition of 9-11 kD N-terminal fragments as fibrils in the kidney, liver, and heart.
Associations Pending Confirmation
Sadaf et al. (2002) found an association between a variant of the APOA1 promoter (the G-to-A difference at position -75) and blood pressure in a study in the United Arab Emirates. Both systolic and diastolic blood pressure varied in a gene-dosage-related manner in individuals of the AA, AG, and GG genotypes, with lowest pressures associated with the GG genotype.
See 107680.0029 for discussion of a possible association between variation in the APOA1 gene and an increase in HDL-C levels.
Utermann et al. (1982) described methods for rapid screening and characterization of variant group A apolipoproteins.
Kessling et al. (1985) failed to find an association between any allele of several RFLPs studied and hypertriglyceridemia.
Buraczynska et al. (1985) found association between an EcoRI polymorphism of the APOA1 gene and noninsulin-dependent diabetes mellitus.
In 4 generations of a Norwegian kindred, Schamaun et al. (1983) found, by 2-D electrophoresis, a variant of apolipoprotein A-I. Codominant inheritance was displayed. One homozygote was identified. There was no obvious cardiovascular disease, even in the homozygote.
Kessling et al. (1988) studied the high density lipoprotein-cholesterol concentrations along with restriction fragment length polymorphisms in the APOA2 and APOA1-APOC3-APOA4 gene cluster in 109 men selected from a random sample of 1,910 men aged 45 to 59 years. They found no significant difference in allelic frequencies at either locus between the groups of individuals with high and low HDL cholesterol levels. They did find an association between a PstI RFLP associated with apoA-I and genetic variation determining the plasma concentration of apoA-I. No significant association was found between alleles for the apoA-II MspI RFLP and apoA-II or HDL concentrations.
Antonarakis et al. (1988) studied DNA polymorphism of a 61-kb segment of 11q that contains the APOA1, APOC3, and APOA4 genes within a 15-kb stretch. Eleven RFLPs located within the 61-kb segment were used by haplotype analysis. Considerable linkage disequilibrium was found. Several haplotypes had arisen by recombination and the rate of recombination within the gene cluster was estimated to be at least 4 times greater than that expected based on uniform recombination. Taken individually, the polymorphism information content (PIC) of each of the 11 polymorphisms ranged from 0.053 to 0.375, while that of their haplotypes ranged between 0.858 and 0.862. (The PIC value, which was introduced by Botstein et al. (1980) in their classic paper on the use of RFLPs as linkage markers, represents the sum of the frequency of each possible mating multiplied by the probability that an offspring will be informative.)
Thompson et al. (1988) investigated the seeming paradox that 2 RFLPs at the A-I/C-III cluster were in strong linkage disequilibrium while a third variant, located between the 2 other markers, appeared to be in linkage equilibrium with these 2 'outside' markers. Thompson et al. (1988) showed that, for the gene frequencies encountered, very large sample sizes would be required to demonstrate negative (i.e., repulsion-phase) linkage disequilibrium. Such numbers are usually difficult to attain in human studies. Therefore, failure to demonstrate linkage disequilibrium by conventional methods does not necessarily imply its absence.
Using a PstI polymorphism at the 3-prime end of the APOA1 gene, Ordovas et al. (1986) found the rarer allele ('3.3-kb band') in 4.1% of 123 randomly selected control subjects and 3.3% of 30 subjects with no angiographic evidence of coronary artery disease. In contrast, among 88 patients who had severe coronary artery disease before age 60, as documented by angiography, the frequency was 32%. It was also found in 8 of 12 index cases of kindreds with familial hypoalphalipoproteinemia. Among all patients with coronary artery disease, 58% had HDL cholesterol levels below the 10th percentile; however, this frequency increased to 73% when patients with the 3.3-kb band were considered.
Smith et al. (1992) investigated the common G/A polymorphism in the APOA1 gene promoter at a position 76 bp upstream of the transcriptional start site (-76). Of 54 subjects whose apoA-I production rates had been determined by turnover studies, 35 were homozygous for a guanosine at this locus and 19 were heterozygous for a guanosine and adenosine (G/A). The apoA-I production rates were significantly lower (by 11%) in the G/A heterozygotes than in the G homozygotes (p = 0.025). However, no effect on HDL cholesterol or apoA-I levels were noted. Differential gene expression of the 2 alleles was tested by linking each of the alleles to the reporter gene chloramphenicol acetyltransferase and determining relative promoter efficiencies after transfection into the human HepG2 hepatoma cell line. The A allele, as well as the G allele, expressed only 68%.
Naganawa et al. (1997) reported 2 haplotypes due to 5 polymorphisms in the intestinal enhancer region of the APOA1 gene in endoscopic biopsy samples from healthy volunteers. The mutant haplotype had a population frequency of 0.44; frequency of wildtype was 0.53. APOA1 mRNA levels were 49% lower in mutant haplotype homozygotes than in wildtype homozygotes, while APOA1 synthesis was 37% lower than wildtype in individuals homozygous for the mutant allele. Heterozygotes had 28% and 41% reductions of mRNA levels and APOA1 synthesis, respectively, as compared to wildtype homozygotes. Expression studies in Caco-2 cells showed a 46% decrease in transcriptional activity in cells containing the mutant constructs, and binding of Caco-2 nuclear proteins in mutant, but not wildtype, sequences. Naganawa et al. (1997) concluded that intestinal APOA1 transcription and protein synthesis were reduced in the presence of common mutations which induced nuclear protein binding.
Retraction
The article by Ajees et al. (2006) describing the crystal structure of human APOA1 was retracted by the publisher because the US Office of Research Integrity found that 'H. M. Krishna Murthy falsified and/or fabricated the protein crystal structure of apolipoprotein A-I reported in this article and the corresponding structure factors and coordinate file deposited in the Protein Data Bank for entry 2A01.'
Franceschini et al. (1980) found hypertriglyceridemia with mildly reduced levels of high density lipoprotein (HDL) levels in father, son, and daughter of an Italian family (619836). The affected persons showed no clinical signs of atherosclerosis and the family had no unusual occurrence of atherosclerotic disease. Analytical isoelectric focusing of HDL apoproteins and 2-dimensional immunoelectrophoresis against apoA antiserum showed quantitative and qualitative changes in apolipoprotein A-I. In the anomalous protein, Weisgraber et al. (1980) found a cysteine residue which is not present in the normal apoprotein. The anomalous protein was designated A-I (Milano) and denoted A-I (cys) by them. This was the first discovered example of variation in the amino acid sequence of a plasma lipoprotein. Serum cholesterol was normal. Weisgraber et al. (1983) showed that cysteine is substituted for arginine at position 173. This change in the protein probably reflects a change of CGC to TGC, since this is the only possibility requiring change of a single nucleotide.
Gualandri et al. (1985) traced the origin of the gene for A-I (Milano) to Limone sul Garda, a small community of about 1,000 persons in northern Italy. In a study of the entire population, 33 living carriers were found, ranging in age from 2 to 81 years. The genealogy showed origin of all cases from a single couple living in the 18th century. Despite low HDL cholesterol levels and increased (though not significantly so) mean level of triglycerides, no evidence of increased atherosclerosis was found.
Shah et al. (2001) formulated recombinant A-I (Milano) in a complex with a naturally occurring phospholipid. Studies in mice and rabbits with experimental atherosclerosis demonstrated that such complexes rapidly mobilized cholesterol and thereby reduced atherosclerotic plaque burden. The antiatherosclerotic effects occurred in animals as rapidly as 48 hours after a single infusion. In humans, Nissen et al. (2003) found that this complex, administered intravenously for 5 doses at weekly intervals, produced significant regression of coronary atherosclerosis as measured by intravascular ultrasound.
Utermann et al. (1982) described a variant apolipoprotein, which they named apoA-I(Marburg). Utermann et al. (1982) found a frequency of about 1 per 750 persons for apoA-I(Marburg) in West Germany (3 heterozygotes in 2,282 unrelated persons). All 3 heterozygotes had hypertriglyceridemia and subnormal HDL cholesterol (619836). Family data from 2 kindreds were consistent with autosomal codominant inheritance.
Rall et al. (1984) demonstrated reduced activation of LCAT (606967) but no reduction in HDL cholesterol or clinical consequences in association with deletion of lysine-107.
Breslow (1988) noted that apoA-I(Marburg) described by Utermann et al. (1982) and the lys107del mutation (apoA-I-Munster2A) described by Rall et al. (1984) are likely identical.
Strobl et al. (1988) described the third case of a glu198-to-lys mutation in the APOA1 gene and the first instance in which a family study was performed, with identification of 5 other persons with the variant in heterozygous form (619836). The mutation appeared to bear no relationship to premature atherosclerosis. Despite the fact that the mutation occurred in a part of the molecule thought to be involved in lipid binding, it bound almost exclusively to HDL as does normal apoA-I.
Breslow (1988) noted that this mutation is designated apoA-I(Munster4).
An apoA-I mutant with electrophoretic mobility similar to that of glu198-to-lys (107680.0003) was found to have a glu136-to-lys substitution (Schamaun et al., 1983; Rall et al., 1986).
Breslow (1988) noted that this mutation is designated apoA-I(Norway).
Utermann et al. (1982) described this apoA-I variant, which they designated apoA-I(Giessen). Utermann et al. (1984) observed defective activation of LCAT (606967) by the Giessen variant of apoA-I. Individuals with the P143R variant in the APOA1 gene have mildly reduced levels of HDL and decreased levels of the mutant protein (619836).
Using a simple and rapid method for the structural analysis of mutant apolipoproteins, von Eckardstein et al. (1989) demonstrated 3 variants in the mature apolipoprotein A-I polypeptide of 243 amino acids: pro3-to-arg (P3R), pro4-to-arg (107680.0008), and pro165-to-arg (107680.0009). All the variant carriers were heterozygous for the mutant. In the case of the pro3-to-arg mutant, the variant proapoA-I was present in increased concentrations as compared to the normal proapoA-I, suggesting that the interspecies-conserved proline residue in position 3 of mature apoA-I is functionally important for the enzymatic conversion of the proprotein to the mature protein. The pro165-to-arg variant was associated with lower levels of apoA-I and HDL cholesterol. The variant protein accounted for only 30% of the total apoA-I in plasma instead of the expected 50% (619836).
Breslow (1988) noted that the P3R mutation is designated apoA-I(Munster3C).
See 107680.0007 and von Eckardstein et al. (1989).
Breslow (1988) noted that the P4R mutation is designated apoA-I(Munster3B).
Von Eckardstein et al. (1989) found that the pro165-to-arg (P165R) variant in the APOA1 gene was associated with lower levels of apoA-I and HDL cholesterol. The variant protein accounted for only 30% of the total apoA-I in plasma instead of the expected 50%. See 107680.0007.
In a family of English-Scottish-Irish extraction, Van Allen et al. (1969) studied a form of amyloidosis (see 105200) in which neuropathy dominated the clinical picture early in the course and nephropathy late in the course. The average age of onset was about 35 years and the average survival after onset was about 12 years, with death ascribable in most cases to renal amyloidosis. Severe peptic ulcer disease occurred in some and hearing loss was frequent. Cataracts were present in several, but vitreous opacities were not observed. The pedigree was typical of autosomal dominant inheritance. In the Iowa or Van Allen type of amyloidosis, Nichols et al. (1987, 1988) found that apolipoprotein A-I is a major constituent of the amyloid. In this condition, the apolipoprotein A-I protein was found to contain a substitution of glycine by arginine at position 26. The mutation of arg for gly26 predicted a guanine-to-cytosine substitution as the nucleotide corresponding to the first base of codon 26 (GGC-to-CGC) of the APOA1 gene. Using PCR and direct sequencing, Nichols et al. (1989, 1990) confirmed the prediction on DNA extracted from paraffin-embedded tissues from 3 members of the kindred who died in the 1960s with amyloid neuropathy. Since the mutation does not alter the restriction pattern of the APOA1 gene, they used PCR with an arg26 allele-specific primer for detection of asymptomatic gene carriers. They demonstrated inheritance of the APOA1 variant through 3 generations of the Iowa kindred and confirmed its association with the development of systemic amyloidosis.
Norum et al. (1980, 1982) studied 2 sisters, aged 30 and 25, with very low HDL and heart failure from coronary artery disease. Both had arcus cornealis, xanthelasmata and extensive infiltrative xanthoma of the neck and antecubital fossa, resembling somewhat the changes of pseudoxanthoma elasticum. The skin histology showed collections of lipid-laden histiocytes. Plasma cholesterol was 177 and 135 mg/dl; HDL cholesterol was 4 and 7 mg/dl. Only traces of apoprotein A-I were detected in whole plasma; in addition, apoprotein C-III was not detectable. The parents and children of the 2 women had low HDL cholesterol and apoA-I levels consistent with heterozygosity. Low levels of HDL cholesterol concentration have been associated with an increased frequency of coronary artery disease even when HDL is no less than 50% of normal (Miller and Miller, 1975). Heart failure without myocardial infarction is unusual in coronary atherosclerosis, especially in young women, suggesting small vessel disease. The patient of Gustafson et al. (1979), although clinically similar, differed by having high apoC-III rather than absent apoC-III.
Karathanasis et al. (1983) showed that the probands in the family of Norum et al. (1982) were both homozygous for a defect in the apoA-I locus, namely, an insertion in an intron. They could identify heterozygotes unequivocally. The parents had the same gene defect; they were not known to be related but both had ancestors of Scottish extraction who lived in the Appalachian mountain region of southeastern Kentucky. When McKusick saw the 2 sisters in 1983, he was impressed that the xanthomatosis of the neck and antecubital fossae simulated the changes of PXE (177850, 264800). The obligatory heterozygotes may be at increased risk of atherosclerosis. Norum and Alaupovic (1984) pointed out that although the only lesion demonstrated is the insertion in the apoA-I gene, the finding of reduced concentrations of both A-I and C-III in heterozygotes suggests that the apoC-III deficiency in the homozygotes is not secondary but due either to mutation also in the apoC-III gene or to an effect of the apoA-I gene on the cis apoC-III gene. Either hypothesis suggests linkage of the 2 loci. Norum (1983) suggested that the gene for apolipoprotein C-II may be in the same cluster on chromosome 11 because it, like C-III, was severely deficient in the 2 sisters. Karathanasis et al. (1983) studied the genomic sequences flanking the APOA1 gene and found that the APOC3 gene (see 107720) lies about 2.6 kb downstream of the 3-prime end of the APOA1 gene. They also showed that the 2 genes are 'convergently transcribed' and that the polymorphism reported by Rees et al. (1983) to be associated with hypertriglyceridemia may be due to a single basepair substitution in the 3-prime-noncoding region of apoC-III mRNA. Forte et al. (1984) cited evidence that the 6.5-kb insert in the APOA1 gene is deleted from its normal position in the promoter region for the closely linked APOC3 gene. Protter et al. (1984) isolated and characterized the APOC3 gene. The coding sequence was found to be interrupted by 3 introns. The authors compared it with the APOA1 gene and sequenced the DNA lying between the 2 genes. Karathanasis et al. (1986) studied the restriction pattern of the APOA4 gene in the sisters with combined apoA-I and apoC-III deficiency. Although apoA-IV had not been demonstrated in the plasma of these patients, the relatively high levels of plasma LCAT activity (40% of normal) and the possible involvement of apoA-IV in LCAT activation suggested that the APOA4 gene of these patients is functionally normal. Karathanasis et al. (1987) demonstrated that these patients had a rearrangement in the form of an inversion containing portions of the 3-prime ends of the APOA1 and APOC3 genes, including the DNA between these genes. The breakpoints were located within the fourth exon of the APOA1 gene and the first intron of the APOC3 gene. The fusion gene was expressed as a fusion mRNA.
Schaefer et al. (1982) studied the plasma lipids of a middle-aged woman who died following coronary artery bypass grafting for atherosclerotic narrowing of multiple arteries. She had markedly reduced high density lipoprotein, no detectable apolipoprotein A-I, normal A-II, and moderately reduced apolipoproteins B and C (see 620058). Both of her children, all 6 of her living sibs, and both parents had reduced apolipoprotein A-I and HDL levels and normal apolipoprotein A-II. Three of the sibs and their mother had coronary disease. The proband had corneal clouding due to diffuse lipid deposits in the epithelial cells; none of the heterozygotes had this finding. The condition in this family differs from Tangier disease (205400; analphalipoproteinemia) in the complete absence of apolipoprotein A-I and normal levels of A-II in the homozygote. Heterozygotes in this condition have reduced A-I only, whereas Tangier heterozygotes have reduced A-I and A-II. Consanguinity in this family, while likely on the basis of geographic isolation, was not proved. In the family reported by Schaefer et al. (1982), Ordovas et al. (1989) demonstrated that all of the APOA1/APOC3/APOA4 gene complex was deleted from a point about 3.1 kb 5-prime to the APOA1 gene to a point 3-prime to the APOA4 gene.
Ladias et al. (1990) detected this variant, apoA-I (Baltimore), in a man with hypoalphalipoproteinemia who was under study for coronary artery disease. A G-to-T substitution in codon 34 of the third exon of the APOA1 gene resulted in an arg10-to-leu (R10L) substitution of mature apoA-I. (ApoA-I is synthesized in the liver and small intestine as a 267-residue preproapolipoprotein. The presegment, 18 amino acid residues long, is cleaved at the time of translation by a signal peptidase. The resulting proapoA-I contains a hexapeptide prosegment covalently linked to the NH(2) terminus of mature apoA-I; it is secreted into plasma and lymph and undergoes extracellular posttranslational cleavage to the mature 243-residue apoA-I.) The mutation changed a CG dinucleotide to CT and therefore was an exception to the CG-to-TG mutation rule, in which methylation/deamination of the C in the CpG dinucleotide results in a C-to-T substitution. The proband was heterozygous for the mutation. The variant was found in 8 members of the family but only 3 were affected (619836).
Funke et al. (1991) studied an otherwise healthy 42-year-old man for massive corneal clouding that resembled that described in patients with fish-eye disease. There was no history in the patient or in his family of precocious coronary artery disease and no evidence of consanguinity; the parents came from different parts of Germany. Funke et al. (1991) identified a homozygous base deletion in the fourth exon of the APOA1 gene as the basic defect responsible for complete absence of HDL from the plasma and corneal opacities (618463). Heterozygous carriers of the base deletion showed approximately half-normal HDL cholesterol concentrations. A guanine residue from codon 202 was deleted, leading to frameshift and premature termination at amino acid 229. The proband's mother and all 3 of his children were heterozygous.
In a Japanese female patient with deficiency of APOA1 and premature atherosclerosis (618463), Matsunaga et al. (1991) demonstrated homozygosity for a nonsense mutation at codon 84 in exon 4 of the APOA1 gene: CAG-to-TAG, gln-to-stop. The patient was also homozygous for another mutation, ala37-to-thr (GCC-to-ACC) in exon 3; this mutation represented a polymorphism because it was found in other persons with normal levels of APOA1 and high density lipoprotein cholesterol. The patient's parents were first cousins.
In an English family with autosomal dominant nonneuropathic systemic amyloidosis (see 105200), Soutar et al. (1992) identified a CTG (leu)-to-CGG (arg) transversion at codon 60. The affected individuals were heterozygotes. The Iowa variant of amyloidosis is another form due to mutation in the APOA1 gene (107680.0010). Soutar et al. (1992) suggested that the systemic nonneuropathic form is the same as the Iowa form, which in turn is the same as the Ostertag type. Indeed, the phenotype appears to be different from that originally described by Van Allen et al. (1969); in the Iowa family, neuropathy dominated the clinical picture early in the course and nephropathy late in the course.
Ng et al. (1994) discovered a novel mutation causing analphalipoprotein A-I deficiency (618463) in a Canadian kindred. The 34-year-old Caucasian proposita, the product of a consanguineous marriage, initially presented at the age of 30 years because of xanthelasmata. In the same year, the patient was diagnosed with bilateral cataracts requiring cataract extraction in the right eye. She also had bilateral subretinal lipid deposition with exudative proliferative retinopathy complicated by bilateral retinal detachments, which were treated surgically. She had a longstanding history of mild imbalance, i.e., unsteadiness. Examination showed mildly thickened Achilles tendons and mild midline cerebellar ataxia. One sister had had a mild myocardial infarction at age 34. Another sister with angina had cerebellar ataxia. High density lipoprotein cholesterol was very low and apoA-I was undetectable. Genomic DNA sequencing of the APOA1 gene identified homozygosity for a nonsense mutation at codon -2, which Ng et al. (1994) designated as Q(-2)X. The mutation was a C-to-T transition in exon 3, which transformed a codon at position -2 relative to the first amino acid of circulating mature apoA-I. The normal sequence at this position encodes glutamine, but the mutated codon encoded premature termination.
In 3 members of a Japanese family with primary intermediate hypoalphalipoproteinemia-2 (619836), Nakata et al. (1993) identified heterozygosity for an insertion of a single C in the run of 7 cytosines between codons 3 and 5 of the mature sequence of the APOA1 gene. The variant, designated APOA1-Tsukuba, resulted in a frameshift and a premature stop at codon 34. The proband, her mother, and maternal aunt had average plasma HDL-C and apoA-I levels of 50% and 53%, respectively, of those of controls.
Romling et al. (1994) found homozygosity for a gln32-to-ter (Q32X) mutation in the APOA1 gene in a 31-year-old woman who presented with no signs of coronary artery or other atherosclerosis. She came from a large Sicilian family with no apparent increased prevalence of myocardial infarction. Among 8 sibs of the proband's heterozygous parents, 7 persons, aged 57 to 73, were alive and had no symptoms of atherosclerotic disease. The parents were first cousins. During her first pregnancy at age 22, the homozygous proband developed bilateral periorbital xanthelasmas, which did not progress after delivery. She had smoked 10 to 12 cigarettes per day since the age of 18 years. Heterozygotes showed half-normal plasma concentrations of HDL cholesterol and apoA-I.
Booth et al. (1996) described a Spanish family with autosomal dominant nonneuropathic hereditary amyloidosis (105200) with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disorder was caused by a previously unreported deletion/insertion mutation in exon 4 of the APOA1 gene encoding loss of residues 60-71 of the normal mature APOA1 and insertion at that position of 2 new residues, valine and threonine. Affected individuals were heterozygous for the mutation and had both normal APOA1 and variant molecules bearing 1 extra positive charge, as predicted from the DNA sequence. The amyloid fibrils were composed exclusively of N-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wildtype sequence. Amyloid fibrils derived from the other 3 known amyloidogenic APOA1 variants (107680.0010, 107680.0016, and 107680.0021) are composed of similar N-terminal fragments. All known amyloidogenic APOA1 variants carry 1 extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this was the first deletion mutation to be described in association with hereditary amyloidosis.
Booth et al. (1996) described a trp50-to-arg variant of APOA1 causing hereditary amyloidosis (105200).
In a 67-year-old Japanese male with corneal opacities, coronary artery disease, and less than 10% of normal APOA1 and HDL cholesterol levels (618463), Huang et al. (1998) found a homozygous mutation in the APOA1 gene. A T-to-A substitution at nucleotide 1762 in exon 4 resulted in a val-to-glu substitution at codon 156. Lecithin:cholesterol acyltransferase activity and cholesterol esterification were less than 40% of normal control values. The proband's elder brother, also homozygous for the mutation, had reduced APOA1 and HDL levels but no clinical evidence of coronary artery disease. The heterozygous son of the proband showed nearly 60% of normal APOA1 and normal HDL cholesterol levels. The position of this and other mutations led the authors to conclude that residues 143-164 are important in APOA1 function, particularly LCAT activation.
This mutation has been designated apolipoprotein A-I (Oita).
One of 4 mutations in the APOA1 gene found by Yamakawa-Kobayashi et al. (1999) as the cause of primary hypoalphalipoproteinemia (618463) was a donor splice site mutation in intron 2, changing the canonical +1 from G to C.
Hamidi Asl et al. (1999) found that autosomal dominant hereditary amyloidosis with a unique cutaneous and cardiac presentation and death from heart failure by the sixth or seventh decade was associated with a 1389T-C transition in exon 4 of the APOA1 gene. The predicted substitution of leu90-to-pro (L90P) substitution was confirmed by structural analysis of amyloid protein isolated from cardiac deposits of amyloid. The subunit protein was composed exclusively of NH2-terminal fragments of the variant APOA1 with the longest ending at residue 94 in the wildtype sequence. Amyloid fibrils derived from 4 previously described APOA1 variants were composed of similar fragments with carboxy-terminal heterogeneity, but contrary to those variants, which all carry one extra positive charge, the leu90-to-pro substitution did not result in any charge modification. The authors considered it unlikely, therefore, that amyloid fibril formation is related to change of charge for a specific residue of the precursor protein. This is in agreement with studies on transthyretin amyloidosis in which no unifying factor, such as change of charge for amino acid residues, has been noted.
The family with the L90P mutation reported by Hamidi Asl et al. (1999) was brought to attention by the case of a 54-year-old woman who presented with recent onset of exertional dyspnea and cutaneous lesions for many years. The skin lesions, which were yellow and maculopapular, first appeared on the forehead and extended rapidly to the face, neck, shoulders, and axillary and antecubital areas. The patient had cardiomegaly, right bundle branch block, concentric thickening of the wall of the left ventricle with a small left ventricular cavity, a typical restrictive hemodynamic pattern on cardiac catheterization, and amyloid deposits on endomyocardial biopsy. A 57-year-old second cousin presented with a 3-year history of extensive cutaneous maculopapular amyloidosis. Petechial purpura was observed on the skin, ocular conjunctiva, tonsil pillars, buccal mucosa, and lips.
Hamidi Asl et al. (1999) described an American kindred in which hereditary amyloidosis showed expression mainly in the skin and heart. The proband was a 33-year-old Caucasian woman who was referred to a dermatologist to evaluate diffuse rash with the appearance of acanthosis nigricans in the axillae. A skin biopsy stained with Congo red revealed the presence of amyloid deposits. The proband's father had a history of cerebral aneurysms at the age of 37 and subsequently was diagnosed as having systemic amyloidosis with multiorgan involvement. He died at the age of 63 with cardiomyopathy and liver and renal failure. The proband had 3 sisters. One, 40 years old, developed brown skin rash in the axillary regions at age 20. The rash progressed to involve the skin of the neck and was associated with petechial hemorrhages and thickening of the skin on the hands. Another sister, age 37, had also been shown to have dermal amyloidosis by a positive skin biopsy. A 42-year-old sister, who had not been medically evaluated, had a raspy voice, a symptom shared by other affected individuals in this family. A sister of the proband's father was a 71-year-old woman with a several-year history of voice changes due to amyloid deposition in the vocal cords proven by biopsy. She also had cutaneous amyloid and had been shown by echocardiography to have hypertrophic cardiomyopathy. The proband's paternal grandmother had the diagnosis of cardiac and vocal cord amyloidosis, and a nephew of the grandmother died of cardiomyopathy at age 52. Subsequently, a daughter of this nephew had the diagnosis of amyloid cardiomyopathy made by endomyocardial biopsy. Characterization of fibrils isolated from skin of the proband identified the amyloid protein as the N-terminal 90 to 100 residues of apolipoprotein A-1. Sequence of the APOA1 gene was normal except for a G-to-C transversion at position 1638, which predicted an arg173-to-pro substitution. This mutation, unlike previously described amyloidogenic mutations, was not in the N-terminal fragment which is incorporated into the fibril. The mutation was at the same residue as in APOA1-Milano (107680.0001), which has an arg173-to-cys substitution but does not result in amyloid formation. Decreased plasma HDL cholesterol levels in carriers of the arg173-to-pro mutation suggested an increased rate of catabolism, as has been shown for the amyloidogenic gly26-to-arg mutation (107680.0010). This suggests that altered metabolism caused by the mutation may be a significant factor in apolipoprotein A-1 fibrillogenesis.
In a patient with systemic nonneuropathic amyloidosis (105200), Obici et al. (1999) identified a T-to-C transition at nucleotide 2069 of the APOA1 gene, resulting in a leu174-to-ser substitution. The proband was affected by amyloid deposits mainly in the heart, requiring transplantation for end-stage congestive heart failure. The amyloid fibrils immunoreacted exclusively with anti-APOA1 antibodies. Obici et al. (1999) identified the same mutation in an affected uncle. The plasma levels of high-density lipoprotein and of apoA-I were significantly lower in the patient than in unaffected individuals. The authors stated that this represents the first case of familial apoA-I amyloidosis in which the mutation occurred outside the polypeptide fragment deposited as fibrils. In the 3-dimensional structure of lipid-free apoA-I, composed of 4 identical polypeptide chains, position 174 of one chain was located near position 93 of an adjacent chain, suggesting that the amino acid replacement at position 174 was permissive for a proteolytic split at the C-terminal of val93.
In the course of studying patients thought to have systemic amyloidosis of the acquired monoclonal immunoglobulin light-chain (AL) type (see 254500) because of the absence of family history, Lachmann et al. (2002) found a new mutation in the APOA1 gene causing renal amyloidosis (105200), ala175 to pro (A175P). The age at presentation with renal failure was 35 years in this English patient. In addition to renal failure, he had hoarseness due to laryngeal amyloid deposits, a feature that commonly occurs in localized AL amyloidosis and that had also been reported in patients with mutations disrupting this particular region of the apolipoprotein A-1 molecule (e.g., Hamidi Asl et al., 1999). Seemingly, sterility was also a problem.
Dastani et al. (2006) studied 54 unrelated French Canadian patients with severe high-density lipoprotein cholesterol (HDL-C) deficiency (619836). Direct sequencing revealed a novel heterozygous APOA1 mutation (E136X) in 3 probands. The mutation was confirmed by MaeI endonuclease digestion. Two of the kindreds were examined (62 subjects) and the E136X mutation was detected in 14 additional individuals. All had a HDL-C level less than the 5th percentile for age- and gender-matched subjects and mild to moderate hypertriglyceridemia. Premature coronary artery disease was documented in probands 1 and 2 and in 3 additional family members.
This variant is classified as a variant of unknown significance because its effect on HDL-C levels has not been confirmed.
Using whole-exome sequencing in 2,636 Icelanders, Helgadottir et al. (2016) identified sequence variants and subsequently examined the variants for association with non-HDL-C, HDL-C, LDL-C, and triglycerides in up to 119,147 Icelanders. One of the novel variants associated with an increase in HDL-C was a C-to-G transversion in the APOA1 gene (chr11.116837074C-G, GRCh38), resulting in a val43-to-leu (V43L) substitution. In Iceland, the variant was found to have a prevalence of 0.7% and to be associated with an increase of HDL-C levels by 0.17 mmol/l (p = 4.5 x 10(-22)) and a similar decrease of non-HDL-C levels (p = 2.5 x 10(-4)).
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