Rare APOA5 mutations--clinical consequences, metabolic and functional effects: an ENID review.

In 2001, a gene encoding a novel apolipoprotein (apo), APOA5, was identified by comparative human/mouse sequencing. The encoded protein, apoAV, had been missed in routine apolipoprotein identification because it occurs at very low plasma concentrations and only DNA analysis led to its identification. Knockout and transgenic mouse models of apoAV showed an inverse relationship with plasma triglyceride levels. In human studies, common APOA5 variants have shown near consistent association with elevated plasma TG levels, confirming apoAV as playing a role in human triglyceride metabolism. Based on mouse knockout models it was predicted that individuals with rare mutations in APOA5 would present with severe hypertriglyceridaemia and apoAV deficiency. However, considering the small number of mutation carriers identified to date, the mode of inheritance is variable and in the recessive form TG levels are within the normal range, and apoAV deficiency only occurs in the homozygous state. Furthermore, penetrance of the mutations is low and appears to require co-inheritance of a common APOA5 TG-raising allele as well as environmental factors for expression of the hypertriglyceridaemia. In this review the clinical and metabolic consequences and phenotype of the three APOA5 mutations reported to date, which lead to premature truncations of apoAV are described. The insight these truncated protein give to the structure-function relationship of apoAV is explored and the relative importance of plasma and liver apoAV discussed.