APOC2 – Familial Apolipoprotein C-II Deficiency

Familial apolipoprotein C-II (apo C-II) deficiency is an autosomal recessive disorder caused by biallelic loss-of-function variants in APOC2, leading to severe hypertriglyceridemia and chylomicronemia. Affected individuals typically present in infancy or early childhood with fasting chylomicronemia, eruptive xanthomas, and risk of pancreatitis. APOC2 encodes apo C-II, a necessary cofactor for lipoprotein lipase (LPL) activity, and its absence results in impaired hydrolysis of triglyceride-rich lipoproteins.

Genetic evidence has been reported in four unrelated probands carrying distinct APOC2 variants: a c.177C>G (p.Tyr59Ter) premature stop in exon 3 (Bari case) (PMID:1971748), a G+1>C splice donor mutation in intron 2 leading to exon 2 skipping (PMID:9126659), a homozygous large deletion of exons 2–4 by Alu–Alu recombination (PMID:25172036), and a homozygous missense p.Leu72Pro disrupting the C-terminal amphipathic helix (PMID:16153625).

Segregation analysis in the intron 2 splice-site family demonstrated homozygosity in the proband and heterozygosity in both parents, with haplotype analysis suggesting inheritance from a common ancestor despite unproven consanguinity (PMID:9126659). Similar recessive segregation was observed in the deletion and missense families, with carrier parents remaining asymptomatic. No additional affected relatives were reported.

The variant spectrum comprises truncating alleles (nonsense and frameshift), splice-site mutations causing exon skipping, large genomic deletions, and critical missense substitutions in the amphipathic helices essential for LPL activation. All reported alleles result in absence or functional impairment of apo C-II, consistent with a loss-of-function mechanism.

Functional studies confirm that truncating mutations produce unstable proteins undetectable in plasma (PMID:1971748), the intron 2 splice mutation causes skipping of the initiation-exon and abolishes protein production (PMID:9126659), large deletions eliminate detectable apo C-II (PMID:25172036), and the Leu72Pro variant severely reduces in vitro LPL activation (PMID:16153625). These data provide moderate experimental support for haploinsufficiency as the pathogenic mechanism.

Integration of genetic and functional findings supports a ClinGen clinical validity category of Moderate for APOC2–related familial apo C-II deficiency. Genetic testing should include sequencing of coding exons and splice sites, coupled with copy-number analysis to detect large deletions. Key Take-home: APOC2 loss-of-function variants reliably predict autosomal recessive apo C-II deficiency and guide targeted management of severe hypertriglyceridemia.

References

• Biochemical and biophysical research communications • 1990 • Identification of the mutation responsible for a case of plasmatic apolipoprotein CII deficiency (Apo CII-Bari). PMID:1971748
• Atherosclerosis • 1997 • A G+1 to C mutation in a donor splice site of intron 2 in the apolipoprotein (apo) C-II gene in a patient with apo C-II deficiency. A possible interaction between apo C-II deficiency and apo E4 in a severely hypertriglyceridemic patient. PMID:9126659
• Clinica chimica acta; international journal of clinical chemistry • 2015 • Apolipoprotein C-II Tuzla: a novel large deletion in APOC2 caused by Alu-Alu homologous recombination in an infant with apolipoprotein C-II deficiency. PMID:25172036
• Clinica chimica acta; international journal of clinical chemistry • 2006 • Missense mutation Leu72Pro located on the carboxyl terminal amphipathic helix of apolipoprotein C-II causes familial chylomicronemia syndrome. PMID:16153625

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