thesisMolecular defects in the lipoprotein lipase (LPL) gene account for a significant proportion of the occurrence of the massive hypertriglyceridemia and other clinical manifestations of the chylomicronemia syndrome. Furthermore, some published reports suggest that the heterozygous state for LPL deficiency leads to a reduced capacity to clear triglyceride-rice lipoproteins from plasma; when this clearance is saturated through dietary or hormonal factors, moderate hypertriglyceridemia may be observed. The LPL gene of four hypertriglyceridemia subjects was examined for the presence of molecular variants. In one subject with the classical presentation of the chylomicronemia syndrome and documented deficiency of LPL activity in post heparin plasma, we have identified a mutation leading to the substitution of glutamic acid for glycine at residue 195 of the mature enzyme. The patient was homozygous for this mutation. By in vitro mutagenesis and transient expression in cultured mammalian cells, it was shown that the protein encoded by this mutated sequence lacked catalytic activity, and data on the homologous enzyme pancreatic lipase indicate that this mutation occurred within the catalytic domain of the enzyme. By contrast, we identified two other mutation in two of the three other hypertriglyceridemic subjects with moderate hypertriglyceridemia that did not appear of functional significance. Therefore, we have found no evidence of role of molecular defects of LPL in these milder cases
