Work

APOA5 frameshift mutation S78fs induces partial nonsense-mediated mRNA decay and predisposition to severe hypertriglyceridemia

Year: 2026

Type: article

Abstract: Hypertriglyceridemia increases the risk of both atherosclerotic cardiovascular disease and acute pancreatitis. Apolipoprotein A5 ( APOA5 ) is a critical regulator of plasma triglyceride metabolism. Although loss-of-function variants in APOA5 are known to cause severe hypertriglyceridemia, the molecular mechanisms underlying phenotypic variability remain incompletely understood. In this study, we investigated a pedigree with severe, fibrate-resistant hypertriglyceridemia to characterize a heterozygous APOA5 variant and elucidate its pathogenic mechanism. Targeted sequencing identified a heterozygous frameshift variant, APOA5 c.230dupT (p.Ser78Glu fs Ter190), as the sole monogenic predisposition segregating with severe hypertriglyceridemia in the pedigree. Haplotype analysis confirmed that carriers were homozygous for the common APOA5*1 haplotype, excluding known triglyceride-raising haplotypes. Functional studies revealed that this variant triggered partial nonsense-mediated mRNA decay, with approximately 60% of mutant transcripts degraded and the remaining escaping NMD to produce a C-terminally truncated protein. Notably, this genetic predisposition rendered carriers exquisite sensitivity to common metabolic stressors, which dramatically amplified triglyceride levels. We report a heterozygous APOA5 frameshift variant that, independently of other genetic modifiers, confers a predisposition to severe HTG. Its pathogenicity arises from combined partial NMD and production of a frameshifted, C-terminally truncated protein, creating a state of heightened metabolic fragility that dramatically amplifies the triglyceride response to environmental triggers. This work underscores the essential role of lifestyle modification in managing such genetic susceptibilities and validates the therapeutic rationale for future targeted therapy.

Source: Human Genomics

DOI: 10.1186/s40246-026-01029-3