APOA5 – Hyperlipoproteinemia Type V

The APOA5 gene encodes a liver-expressed apolipoprotein that is critical for triglyceride homeostasis. Loss-of-function variants in APOA5 impair lipolysis of triglyceride-rich lipoproteins, leading to marked hypertriglyceridemia and chylomicron accumulation characteristic of Hyperlipoproteinemia Type V. Clinically, this manifests with plasma triglyceride levels often exceeding 30 mmol/L, increased risk of acute pancreatitis, and premature cardiovascular disease.

A homozygous frameshift mutation c.427del (p.Arg143AlafsTer57) was identified in a 12-year-old Pakistani boy with severe type V hyperlipoproteinemia refractory to fibrate therapy but responsive to a very low-fat diet (PMID:27678447). In an independent review of four families, a homozygous p.Gln148Ter mutation caused severe hyperlipidemia, while heterozygous p.Gln139Ter carriers exhibited moderate type V hyperlipoproteinemia and reduced lipoprotein lipase activity (PMID:16531747).

Segregation analysis in the consanguineous pedigree demonstrated co-segregation of truncating APOA5 alleles with phenotype: both parents and one sibling heterozygotes had intermediate hypertriglyceridemia, confirming autosomal recessive inheritance and variable expressivity.

Functional assays reveal that p.Gln139Ter exerts a dominant-negative effect on lipolysis by disrupting APOA5–lipoprotein interactions and impairing LPL activation (PMID:16200205). In vitro, truncated APOA5 variants fail to enhance triglyceride hydrolysis, consistent with haploinsufficiency and loss of function.

In apoa5-knockout mice, adeno-associated virus–mediated expression of wild-type but not the G162C (p.Gly185Cys) variant rescues hypertriglyceridemia, underscoring the necessity of intact APOA5 for normal lipid metabolism (PMID:25127531). Structural studies of the C-terminal domain show preserved folding with altered lipid-binding kinetics, elucidating mechanisms by which truncations compromise function (PMID:17401142).

Overall, the association between APOA5 and type V hyperlipoproteinemia is classified as Moderate based on six probands across three unrelated families, segregation in pedigrees, and concordant functional data. Genetic evidence is Moderate: multiple truncating variants in biallelic and heterozygous states correlate with disease (reaching a genetic cap of ~6 cases). Functional evidence is Moderate: in vitro LPL activation assays and murine rescue studies confirm loss of APOA5 activity. Key take-home: recessive APOA5 truncating variants cause severe type V hyperlipoproteinemia, while heterozygotes have moderate risk, supporting its use in genetic diagnosis, family screening, and personalized management.

References

• Journal of clinical lipidology | 2016 | Frameshift mutation in the APOA5 gene causing hypertriglyceridemia in a Pakistani family: Management and considerations for cardiovascular risk. PMID:27678447
• Current opinion in lipidology | 2006 | APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency. PMID:16531747
• The Journal of clinical investigation | 2005 | Give me A5 for lipoprotein hydrolysis! PMID:16200205
• Arteriosclerosis, thrombosis, and vascular biology | 2005 | Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. PMID:15591215
• Arteriosclerosis, thrombosis, and vascular biology | 2014 | Aberrant hetero-disulfide bond formation by the hypertriglyceridemia-associated p.Gly185Cys APOA5 variant (rs2075291). PMID:25127531
• The Journal of biological chemistry | 2007 | The C terminus of apolipoprotein A-V modulates lipid-binding activity. PMID:17401142

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