Objective: To provide phenotypic and functional data in new patients with APOA5 mutations and to identify genetic and metabolic factors influencing their phenotypic expression.
Methods and results: By sequencing APOA5 gene in a cohort of 286 hyperchylomicronemic subjects, free of LPL or APOC2 mutations, we identified 4 unrelated carriers of the Q97X mutation (3 heterozygotes and 1 homozygote) and one heterozygote with a new L242P mutation. Postheparin LPL activity level was reduced by about 50% in Q97X heterozygotes and more than 90% in the Q97X homozygote, but was normal in the L242P patient after resolution of hyperchylomicronemia. Plasma apoAV was undetectable in the Q97X homozygote and in the normal range in the L242P and Q97X heterozygous carriers. In Western blot studies, the association of apoAV with plasma lipoproteins was altered in Q97X heterozygous carriers but not in the L242P carrier. Hyperchylomicronemic heterozygotes for both mutations carried an additional APOA5 variant haplotype and/or APOE variant (E2 or E4). Type 2 diabetes or metabolic syndrome were not a major phenotypic determinant.
Conclusions: The L242P mutation was present in a hyperchylomicronemic proband but its causal involvement remains to be established. The Q97X mutation was clearly involved in hyperchylomicronemia with evidence of concomitant altered intravascular lipolysis, and a complete apoAV deficiency in the homozygote. The phenotypic expression variability of APOA5 mutations was mostly influenced by compound heterozygosity with APOA5 variant haplotypes plus additional genetic factors, and in a lesser extent by the metabolic environment.