Missense mutation Leu72Pro located on the carboxyl terminal amphipathic helix of apolipoprotein C-II causes familial chylomicronemia syndrome

BackgroundChylomicronemia syndrome can be caused by 2 autosomal recessive disorders — lipoprotein lipase (LPL) deficiency and apolipoprotein C-II (apo C-II) deficiency.MethodsWe described 2 siblings with chylomicronemia syndrome of a consanguineous family. To determine the molecular basis of chylomicronemia syndrome in this family, we performed direct DNA sequencing of the LPL and APOC2 genes of the proband.ResultsA novel homozygous mutation, Leu72Pro, in the APOC2 gene was found in both siblings whereas their parents were carriers. No LPL mutations were detected in the siblings. Apo C-II contains 3 amphipathic alpha helices; the C-terminal alpha helix is composed of residues 64 to 74. Substitution of residue 72 from a helix former leucine to a helix breaker, proline, is predicted to change the secondary structure of the C-terminal helix and subsequently alter the interaction between apo C-II and LPL.ConclusionsTo our knowledge, Leu72Pro is the first missense mutation identified in the C-terminal of apo C-II. The result is consistent with the current biochemical and structural findings that the C-terminal helix of apo C-II is important for activation of LPL.