HGNC Approved Gene Symbol: APOC2
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:44,946,051-44,949,565 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | Hyperlipoproteinemia, type Ib | 207750 | Autosomal recessive | 3 |
Apolipoprotein C-II (apoC-II) is a necessary cofactor for the activation of lipoprotein lipase (LPL; 238600), the enzyme that hydrolyzes triglycerides in plasma and transfers the fatty acids to tissues.
Using a mixed oligonucleotide probe corresponding to possible codons for apoC-II amino acids, Jackson et al. (1984) isolated a cDNA clone encoding human apoC-II from an adult human liver cDNA library. The APOC2 cDNA sequence encodes a deduced 79-amino acid protein. Using synthetic oligonucleotides as probes, Sakaguchi et al. (1984) isolated APOC2 from a human cDNA library.
Using 2-dimensional gel electrophoresis and immunoblot analysis, Fojo et al. (1986) identified 4 major plasma isoforms of apoC-II that result from posttranslational modification. Neuraminidase studies showed that 2 of the isoforms are early secreted sialic acid-containing glycoproteins. Fairwell et al. (1987) synthesized the complete amino acid sequence of apolipoprotein C-II by the solid-phase method using phenylacetamidomethyl-resin. The synthetic protein had the same functional properties as the native protein.
Fojo et al. (1987) determined the complete nucleic acid sequence of the APOC2 gene and determined that it contains 4 exons.
Jackson et al. (1984) provisionally assigned the APCO2 gene to chromosome 19 by Southern blot analysis of DNA from human-rodent somatic cell hybrids. Using human-mouse somatic cell hybrids, Sakaguchi et al. (1984) found that the APOC2 gene segregated with chromosome 19.
Using a TaqI polymorphism in an APOC2 cDNA probe, Myklebost et al. (1984) demonstrated close linkage of APOE and APOC2 (maximum lod, sexes combined = 4.52 at theta = 0.0). The APOE locus was 'marked' by apoE protein variants. Donald et al. (1985) used APOC2 RFLPs to study inheritance of the gene in families segregating for loci on chromosome 19. Close linkage with C3 (120700) was excluded (maximum lod at male recombination fraction of 0.25-0.30) and no linkage with familial hypercholesterolemia (143890) was found. Close linkage to Lutheran (111200) and secretor (182100) and probably less close linkage to Lewis (618983) was found. The order FHC--C3--(Lu, Se, APOC2) was suggested. Ball et al. (1985) found close linkage between PEPD (170100) and APOC2. Shaw et al. (1985) found a maximum lod score of 7.877 at 4% recombination for linkage of APOC2 to myotonic dystrophy (DM1; 160900), placing APOC2 at 19p13-q13. Johnson et al. (1989) observed recombination in a family which indicated that DM is distal to APOC2. Smit et al. (1988) presented a map of the apolipoprotein E-C1-C2 gene cluster on chromosome 19: 5-prime--APOE--4.3 kb--APOC1--6 kb--APOC1 pseudogene--about 22 kb--APOC2--3-prime. The APOE gene is closest to the centromere in this cluster, which spans approximately 48 kb.
By in situ hybridization, Das et al. (1987) found that the APOC2 gene was located in the 19q13.3 band. By fluorescence in situ hybridization, Trask et al. (1993) determined that the APOC2 gene is in 19q13.2.
Using a cDNA clone for APOC2, Humphries et al. (1984) could demonstrate no major deletion in or around the APOC2 gene in 2 unrelated persons with familial apoC-II deficiency (207750), which is also called hyperlipoproteinemia type IB. Linkage of the deficiency with a RFLP indicated, however, that the defect causing apoC-II deficiency was in, or closely linked to, the APOC2 gene. By restriction enzyme analysis in 2 patients with apoC-II deficiency, Fojo et al. (1984) found that the APOC2 gene was present and no insertional or deletional abnormality was detected.
In patients with hyperlipoproteinemia type IB, Fojo et al. (1989) and Tuzgol et al. (1994) identified mutations in the APOC2 gene (see, e.g., 608083.0002).
Xiong et al. (1991) demonstrated that the sequence of the APOC2 gene in a normal Japanese male is identical to that in a normal Caucasian (Wei et al., 1985), and that the sequence of the APOC2 gene in the chimpanzee differs by only 3 nucleotides from the normal Japanese and Caucasian sequence. In 2 Japanese patients with apoC-II deficiency originally described by Yamamura et al. (1979) and in a Venezuelan patient with apoC-II deficiency previously reported by Posner et al. (1986), Xiong et al. (1991) identified multiple mutations and deletions in the APCO2 gene. However, at the amino acid level, the Japanese and Venezuelan patients were identical; the DNA-deduced amino acid sequences predicted a prematurely terminated, 17-amino acid frameshifted polypeptide instead of a 79-amino acid peptide. The authors suggested that the mutant alleles in the Japanese and Venezuelan patients arose more than 500,000 years ago from a common origin and that the persistence of the mutant alleles speaks against the occurrence of a bottleneck in the past. Furthermore, they suggested that the finding of one allele in Japan and the other in a Venezuelan Caucasian is more consistent with the multiregional evolution model of modern human origins (Wolpoff et al., 1984) than with the 'out of Africa' or complete-replacement model (Stringer and Andrews, 1988). Although it is generally thought that modern humans originated in Africa, the former model assumes that the transformation occurred gradually by gene flow and natural selection whereas the latter suggests that there was a complete replacement of indigenous archaic populations by modern Africans.
Menzel et al. (1986) showed that about 12% of Americans of African ancestry have a variant of apoC-II, an isoform with substitution of glutamine for lysine at residue 55. This isoform could have been generated by either of 2 single-base exchanges.
Baggio et al. (1986) studied a brother and sister, aged 41 and 39 years, respectively, with hyperlipoproteinemia type IB (207750). Plasma triglycerides and chylomicrons were markedly elevated, whereas LDL and HDL were decreased. The brother had recurrent bouts of abdominal pain, often with eruptive xanthomas; the sister, identified by family screening, was asymptomatic. Both had hepatosplenomegaly. A variant of apoC-II, apoC-II(Padova), with lower apparent molecular weight and more acidic isoelectric point was found in both by 2-dimensional gel electrophoresis. The marked hypertriglyceridemia was corrected by infusion of normal plasma or the injection of a biologically active synthesized 44- to 79-amino acid residue peptide fragment of apoC-II. The effect persisted for 13 to 20 days after injection of the synthetic peptide. Fojo et al. (1989) sequenced the apoC-II(Padova) gene after amplification by the polymerase chain reaction and identified a 3002A-G transition in exon 3, resulting in a premature termination codon (TAA) at a position corresponding to amino acid 37 of the mature apoprotein. As a result, the apoprotein is a truncated 36-amino acid protein that is unable to activate lipoprotein lipase.
In an Italian kindred with apoC-II deficiency, Tuzgol et al. (1994) identified homozygosity for a 3002C-A transversion in the APOC2 gene, resulting in the change of codon 37 from TAC (tyr) to TAA (stop). As a result, a truncated protein was synthesized that lacked the part of the molecule that activates LPL. The parents of the proband were first cousins from Siculiana, a small village in Sicily. In the original kindred from Padova studied by Fojo et al. (1989), Sicilian extraction and consanguinity were not reported. However, since the father of the 2 affected probands was adopted, the presence of Sicilian ancestry could not be excluded. Tuzgol et al. (1994) made reference to the same mutation in another patient originating from Siculiana in whom a genetic relationship to any of the other families was not known. (See also 608083.0008).
Connelly et al. (1987) described a new variant of apoC-II, apoC-II(St. Michael), in a brother and sister with hyperlipoproteinemia type IB (207750) born of white, Anglo-Saxon parents who were first cousins once removed. The sister, aged 60, had a 10-year history of lipemia. While on oral contraceptives, she had 2 attacks of epigastric pain with markedly elevated serum amylase activity that was diagnosed as pancreatitis. A brother, aged 61, had lipemia, recurrent acute pancreatitis, and diabetes mellitus. ApoC-II in these sibs differed from the normal at residue 70, where glutamine was replaced by proline and the sequence terminated with proline as amino acid residue 96. These findings were consistent with a base insertion in the apoC-II gene and a subsequent translation reading frameshift. Both patients had significant ischemic vascular disease, a finding different from that in other homozygotes for apoC-II deficiency. Both were homozygous for apoE*4.
In subsequent studies of the family with hyperlipoproteinemia type IB (207750) reported by Cox et al. (1978), Connelly et al. (1987) identified 14 homozygotes and 23 obligate heterozygotes in the extended pedigree. Their plasma contained a unique apoC-II (designated Toronto, according to the system for hemoglobins) that had an apparent pI of 5.54 instead of 4.88 as in normal apoC-II. It was found that the sequence of apoC-II(Toronto) was identical to that of normal apoC-II from residues 1-68. It differs from residue 69, where asp69-gln70-val71-leu72-ser73-val74-leu75-lys76-gly77-glu78-glu79 is replaced by thr69-lys70-phe71-phe72-leu73-cys74. This change is consistent with the deletion of a nucleotide in the codon for either thr68 or asp69 and a resulting translation reading frameshift. Thus, it show similarities to apoC-II(St. Michael). In the apoC-II(Toronto), Cox et al. (1988) demonstrated a deletion of 1 base in the codon for amino acid threonine-68, causing an alteration of 6 amino acids and a premature termination of the protein at amino acid 74.
Fojo et al. (1988) analyzed the DNA, RNA, and protein of apoC-II in a patient with apoC-II deficiency (207750) of the Hamburg type. By immunoblotting and immunohistochemical analysis, a marked reduction in plasma and intrahepatic C-II apolipoprotein was demonstrated. Northern, slot blot, and in situ hybridization studies showed, furthermore, low levels of a normal-sized apoC-II mRNA. No major rearrangement of apoC-II gene was detected by Southern blotting. Sequence analysis of apoC-II genomic clones showed a G-to-C substitution within the donor splice site of intron 2. This base substitution resulted in the formation of a new DdeI and loss of an HphI restriction enzyme cleavage site. Beil et al. (1992) characterized the clinical and biochemical features of 3 sibs in a kindred with severe hypertriglyceridemia due to apolipoprotein C-II deficiency caused by apoC-II(Hamburg).
Fojo et al. (1988) cloned and sequenced the APOC2 gene from an affected member of a family in Nijmegen, the Netherlands, with deficiency of apoC-II (207750). They demonstrated deletion of a guanosine at base 2943 in the third exon of the APOC2 gene, resulting in the loss of a normal HphI site, a shift in the reading frame, introduction of a premature termination codon, and the formation of a truncated 17-amino acid C-II apolipoprotein. Since the lipoprotein lipase activating domains of the protein are located to amino acids 55-78, this abnormally truncated protein, if secreted, would be nonfunctional as a cofactor for lipoprotein lipase. The proband was found to be homozygous for the base deletion mutation. Since the postheparin plasma lipoprotein lipase activity was reduced even after exogenous C-II was added, it is possible that the truncated 17-amino acid protein is indeed secreted into plasma and acts as an inhibitor, rather than an activator, of lipoprotein lipase.
In the proband from a black Senegalese Paris kindred with apoC-II deficiency (207750), Fojo et al. (1989) identified an A-to-G transition that changed the initiation AUG (methionine) to GUG (valine). Potential initiation of translation at the closest in-frame methionine codon eliminated the entire signal peptide and the first 8 amino-terminal residues of apoC-II, thus preventing secretion of apoC-II into the plasma. The proband was homozygous for the defect.
In an Italian family with 2 sibs with an abnormally high level of triglycerides and total deficiency of plasma C-II (207750), Crecchio et al. (1990) identified a C-G mutation in the third exon of the APOC2 gene, causing premature termination. Truncated at amino acid 36 of the mature form, the protein lost its functional domains, became inefficient, and could not be detected in plasma because of its high instability. The mutation destroyed an RsaI site.
Tuzgol et al. (1994) stated that the nonsense mutation in the APOC2 gene in apolipoprotein C-II(Bari) involves a 3002C-G transversion, resulting in the change of codon 37 from TAC (tyr) to TAG (stop). The codon involved is precisely the same as that in apolipoprotein C-II(Padova) (608083.0002) which has been reported in patients of Sicilian descent; the Bari variant was discovered in a patient of Sicilian descent. The nucleotides surrounding these mutations are GC rich and the presence of GC dinucleotides may serve as a potential hotspot for mutations.
Hegele et al. (1991) described a lys19-to-thr mutation in 5 hyperlipidemic patients: 1 with type III, 3 with type IV, and 1 with type V hyperlipoproteinemia. All were heterozygous for the mutation, and all were found to have both the normal apoC II isoform and the mutant isoform, whose isoelectric point was consistent with a single charge change. The presence of this mutation in unrelated hyperlipidemic patients of various racial backgrounds suggested that, in combination with other factors such as mutations in apolipoprotein E, it likely plays a role in the development of hyperlipoproteinemias.
In 3 unrelated patients with hyperlipidemia, Pullinger et al. (1993) found heterozygosity for a G-A change in the APOC2 gene, resulting in a glu38-to-lys (E38K) substitution. The new variant was referred to as apolipoprotein C-II (San Francisco). The mutation imparted to the apoC-II molecule a major change in charge, but functional studies showed no change in enzyme activity. The authors termed the modified protein a 'charge variant isoform.' Each patient had hypercholesterolemia and hypertriglyceridemia, and 1 patient was also found to have the Q55K (608083.0001) mutation. The change was not identified in 192 controls DNA samples, and is thus not a common polymorphism. Pullinger et al. (1993) noted that the relation of the San Francisco APOC2 variant to the subjects with hyperlipidemia was unclear.
In a 26-year-old man with hyperlipoproteinemia type IB (207750), whose parents were first cousins, Inadera et al. (1993) identified a T-C transition in the APOC2 gene, resulting in a trp26-to-arg (W26R) change.
In an infant with severe hyperlipoproteinemia type IB (207750) and a 'lipid encephalopathy,' Wilson et al. (2003) identified a homozygous 1118C-A change in the APOC2 gene, resulting in a tyr63-to-ter (Y63X) mutation. The patient had severe intracerebral lipid deposition and was neurologically impaired. Her parents, who were related, and unaffected sibs were heterozygous for the mutation.
APOLIPOPROTEIN C-II (BETHESDA). See Sprecher et al. (1984).
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