Deficiency of
apoprotein A-V (
apoA-V) can cause
hypertriglyceridemia. In an 11 months old boy presenting with a severe
hypertriglyceridemia, a formerly unknown 24
nucleotide deletion in exon 2 of the APOA5 gene was detected. The homozygous mutation results in an eight
amino acid loss in the
signal peptide sequence (c.16_39del; p.Ala6_Ala13del). Screening of control persons proved that this deletion is a rare mutation.
Hypertriglyceridemia in the patient was only found at the time when he was breast fed, while after weaning,
triglyceride levels were close to normal. Under both dietary conditions,
apoA-V protein was undetectable in plasma while post-
heparin plasma
lipoprotein lipase activity was normal. Expression analysis of normal and mutated
protein by Western blot and immunofluorescence in
apoA-V deficient primary hepatocytes revealed that, due to changes in the
signal peptide, mutated
apoA-V was intracellularly missorted to lipid droplets and not secreted. Wild type
apoA-V, instead, was not targeted to lipid droplets but transported via endosomal compartments to the plasma membrane for secretion. It is concluded that the c.16_39del mutation in the APOA5 gene leads to hepatic missorting and impaired secretion, which consequently results in undetectable
apoA-V plasma levels. The absence of
apoA-V in plasma leads under conditions of fat-rich diets to severe chylomicronemia, suggestive for a modulatory role of
apoA-V for
lipoprotein lipase mediated intravascular
triglyceride lipolysis.