Alternative titles; symbols
ORPHA: 309020, 444490; DO: 0111418;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.32 | Hyperlipoproteinemia, type Ib | 207750 | Autosomal recessive | 3 | APOC2 | 608083 |
A number sign (#) is used with this entry because of evidence that apolipoprotein C-II deficiency, or apolipoprotein type IB, is caused by homozygous or compound heterozygous mutation in the APOC2 gene (608083) on chromosome 19q13.
Clinically and biochemically, apoC-II deficiency closely simulates lipoprotein lipase deficiency, or hyperlipoproteinemia type I (238600), and is therefore referred to as hyperlipoproteinemia type IB.
Breckenridge et al. (1978) reported the first case of complete deficiency of apoC-II and high levels of triglycerides, in a 59-year-old man who had had chronic, gnawing, epigastric pain from the age of 18 years and diabetes for 11 years. His parents were second cousins. Injection of exogenous high-density lipoprotein reduced plasma triglycerides to values close to normal. In an inbred kindred of British origin, ascertained through a patient with chronic pancreatitis, Cox et al. (1978) found 8 homozygotes for apoC-II deficiency (including the proband). They all showed marked fasting chylomicronemia and triglyceridemia. Five of the 8 had suffered one or more attacks of pancreatitis, beginning at ages varying from 6 to 39 years. Heterozygotes could be identified by the ratio of apoC-II to apoC-III in VLDL and by the plasma lipoprotein lipase activation test. They had no xanthomas. Cox et al. (1978) suggested that the diet of the affected persons, who lived in the Caribbean, probably had until recently protected them from the ill effects of their genetic disease. If less than 15% of calories were derived from fat, reduction in triglycerides could be achieved.
Yamamura et al. (1979) described affected Japanese sister and brother, aged 13 and 15 years, respectively, from a first-cousin mating. Clinically normal, they were ascertained because of serum turbidity from chylomicronemia. Deficiency of apolipoprotein C-II was demonstrated. Heterozygotes had no abnormality of plasma lipid and lipoproteins in spite of reduced plasma apolipoprotein C-II. Saku et al. (1984) concluded that xanthomas and hepatosplenomegaly are less common in C-II anapolipoproteinemia than in lipoprotein lipase deficiency.
Baggio et al. (1986) studied a brother and sister, aged 41 and 39 years, respectively, with hyperlipoproteinemia type IB. 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 patients. 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.
Capurso et al. (1980, 1988) described 2 cases of apoC-II deficiency. Capurso et al. (1988) found that although apoC-II was undetectable in the plasma, apoC-II could be detected within the enterocytes of the intestinal mucosa. Nonfunctional mutant forms of apoC-II were detected in the plasma of apoC-II-deficient patients by Maguire et al. (1984). Although the molecular masses of these forms of the protein were similar to that of the functional protein, they did not activate lipoprotein lipase, could not form insoluble antigen-antibody complexes with polyclonal antibodies to apoC-II, and showed abnormal behavior in polyacrylamide gel isoelectric focusing.
Ohno et al. (1989) described the case of an infant discovered in the neonatal period to have apoC-II deficiency. Milky serum had been noticed at the time of serum bilirubin measurement 6 days after birth. At 7 days, he already showed eruptive xanthomas at many sites.
Wilson et al. (2003) reported an infant with apoC-II deficiency with massive hyperchylomicronemia and a severe 'lipid encephalopathy.' She presented at age 5 weeks with lethargy, macrocephaly, and marked hepatosplenomegaly. Drawn blood was grossly hyperlipemic ('strawberry cream-colored') and showed severe hypertriglyceridemia and hypercholesterolemia. Cranial MRI showed fatty collections in the posterior chambers of the eyes, marked cerebral atrophy, and extradural collections of fatty deposits. She showed severe neurologic abnormalities and developmental delay. Although a low-fat diet achieved biochemical control, she remained neurologically impaired. In the patient and her younger sister, Wilson et al. (2003) identified a homozygous mutation in the APOC2 gene (608083.0012). The parents, who were related, and all unaffected sibs were heterozygous for the mutation.
In 2 families with apoC-II deficiency, Humphries et al. (1984) found linkage to the APOC2 structural gene on chromosome 19.
In studies of the family with hyperlipoproteinemia type IB reported by Cox et al. (1978), Connelly et al. (1987) identified 14 homozygotes and 23 obligate heterozygotes in the extended pedigree. In affected members of this family, Connelly et al. (1987) and Cox et al. (1988) demonstrated a 1-bp deletion in the APOC2 gene (608083.0004).
In a patient with the apoC-II(Padova) variant, such as those described by Baggio et al. (1986), Fojo et al. (1989) identified a mutation in the APOC2 gene (608083.0002).
Johansen et al. (2012) resequenced hypertriglyceridemia-associated candidate genes in 413 adult Canadian patients of European ancestry with plasma triglyceride levels greater than the 95th percentile and in 324 population-based controls. Rare nonsynonymous variants were most abundant in genes established in hypertriglyceridemia pathophysiology, including APOC2, and were in large excess among hypertriglyceridemic patients compared to controls (2.3-fold increase; p = 0.0050). The authors stated that their findings supported a cumulative burden of rare variants in both known and novel genes in human polygenic hypertriglyceridemia.
Baggio, G., Manzato, E., Gabelli, C., Fellin, R., Martini, S., Enzi, G. B., Verlato, F., Baiocchi, M. R., Sprecher, D. L., Kashyap, M. L., Brewer, H. B., Jr., Crepaldi, G. Apolipoprotein C-II deficiency syndrome: clinical features, lipoprotein characterization, lipase activity, and correction of hypertriglyceridemia after apolipoprotein C-II administration in two affected patients. J. Clin. Invest. 77: 520-527, 1986. [PubMed: 3944267] [Full Text: https://doi.org/10.1172/JCI112332]
Breckenridge, W. C., Little, J. A., Steiner, G., Chow, A., Poapst, M. Hypertriglyceridemia associated with deficiency of apolipoprotein C-II. New Eng. J. Med. 298: 1265-1273, 1978. [PubMed: 565877] [Full Text: https://doi.org/10.1056/NEJM197806082982301]
Capurso, A., Mogavero, A. M., Resta, F., Di Tommaso, M., Taverniti, P., Turturro, F., La Rosa, M., Marcovina, S., Catapano, A. L. Apolipoprotein C-II deficiency: detection of immunoreactive apolipoprotein C-II in the intestinal mucosa of two patients. J. Lipid Res. 29: 703-711, 1988. [PubMed: 3171393]
Capurso, A., Pace, L., Bonomo, L., Catapano, A., Schiliro, G., La Rosa, M., Assmann, G. New case of apolipoprotein C-II deficiency. (Letter) Lancet 315: 268 only, 1980. Note: Originally Volume I. [PubMed: 6101731] [Full Text: https://doi.org/10.1016/s0140-6736(80)90768-0]
Connelly, P. W., Maguire, G. F., Hofmann, T., Little, J. A. Structure of apolipoprotein C-II(Toronto), a nonfunctional human apolipoprotein. Proc. Nat. Acad. Sci. 84: 270-273, 1987. [PubMed: 3467353] [Full Text: https://doi.org/10.1073/pnas.84.1.270]
Cox, D. W., Breckenridge, W. C., Little, J. A. Inheritance of apolipoprotein C-II deficiency with hypertriglyceridemia and pancreatitis. New Eng. J. Med. 299: 1421-1424, 1978. [PubMed: 213719] [Full Text: https://doi.org/10.1056/NEJM197812282992601]
Cox, D. W., Wills, D. E., Quan, F., Ray, P. N. A deletion of one nucleotide results in functional deficiency of apolipoprotein CII(apo CII Toronto). J. Med. Genet. 25: 649-652, 1988. [PubMed: 3225819] [Full Text: https://doi.org/10.1136/jmg.25.10.649]
Fojo, S. S., Lohse, P., Parrott, C., Baggio, G., Gabelli, C., Thomas, F., Hoffman, J., Brewer, H. B., Jr. A nonsense mutation in the apolipoprotein C-II(Padova) gene in a patient with apolipoprotein C-II deficiency. J. Clin. Invest. 84: 1215-1219, 1989. [PubMed: 2477392] [Full Text: https://doi.org/10.1172/JCI114287]
Humphries, S. E., Williams, L., Myklebost, O., Stalenhoef, A. F. H., Demacker, P. N. M., Baggio, G., Crepaldi, G., Galton, D. J., Williamson, R. Familial apolipoprotein CII deficiency: a preliminary analysis of the gene defect in two independent families. Hum. Genet. 67: 151-155, 1984. [PubMed: 6547689] [Full Text: https://doi.org/10.1007/BF00272990]
Johansen, C. T., Wang, J., McIntyre, A. D., Martins, R. A., Ban, M. R., Lanktree, M. B., Huff, M. W., Peterfy, M., Mehrabian, M., Lusis, A. J., Kathiresan, S., Anand, SS., Yusuf, S., Lee, A.-H., Glimcher, L. H., Cao, H., Hegele, R. A. Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia. Circ. Cardiovasc. Genet. 5: 66-72, 2012. [PubMed: 22135386] [Full Text: https://doi.org/10.1161/CIRCGENETICS.111.960864]
Maguire, G. F., Little, J. A., Kakis, G., Breckenridge, W. C. Apolipoprotein C-II deficiency associated with nonfunctional mutant forms of apolipoprotein C-II. Canad. J. Biol. 62: 847-852, 1984.
Ohno, M., Ishibashi, S., Nakao, K., Nozue, T., Nonomura, K., Yamada, N., Aburatani, H., Shimano, H., Murase, T. A neonatal case of apolipoprotein C-II deficiency. Europ. J. Pediat. 148: 550-552, 1989. [PubMed: 2501098] [Full Text: https://doi.org/10.1007/BF00441556]
Saku, K., Cedres, C., McDonald, B., Hynd, B. A., Liu, B. W., Srivastava, L. S., Kashyap, M. L. C-II anapolipoproteinemia and severe hypertriglyceridemia: report of a rare case with absence of C-II apolipoprotein isoforms and review of the literature. Am. J. Med. 77: 457-462, 1984. [PubMed: 6475985] [Full Text: https://doi.org/10.1016/0002-9343(84)90102-5]
Stalenhoef, A. F. H., Casparie, A. F., Demacker, P. N. M., Stouten, J. T. J., Lutterman, J. A., van't Laar, A. Combined deficiency of apolipoprotein C-II and lipoprotein lipase in familial hyperchylomicronemia. Metabolism 30: 919-926, 1981. [PubMed: 7266379] [Full Text: https://doi.org/10.1016/0026-0495(81)90072-x]
Wilson, C. J., Priore Oliva, C., Maggi, F., Catapano, A. L., Calandra, S. Apolipoprotein C-II deficiency presenting as a lipid encephalopathy in infancy. Ann. Neurol. 53: 807-810, 2003. [PubMed: 12783430] [Full Text: https://doi.org/10.1002/ana.10598]
Yamamura, T., Sudo, H., Ishikawa, K., Yamamoto, A. Familial type I hyperlipoproteinemia caused by apolipoprotein C-II deficiency. Atherosclerosis 34: 53-65, 1979. [PubMed: 227429] [Full Text: https://doi.org/10.1016/0021-9150(79)90106-0]