Familial chylomicronemia (type I hyperlipoproteinemia) due to a single missense mutation in the lipoprotein lipase gene.

Complete deficiency of lipoprotein lipase (LPL) causes the chylomicronemia syndrome. To understand the molecular basis of LPL deficiency, two siblings with drastically reduced postheparin plasma lipolytic activities were selected for analysis of their LPL gene. We used the polymerase chain reaction to examine the nine coding LPL exons in the two affected siblings and three relatives. DNA sequence analysis revealed a single nucleotide change compared with the normal LPL cDNA: a G----A substitution at nucleotide position 680. This transition caused a replacement of glutamic acid for glycine at amino acid residue 142 of the mature LPL protein. Amino acid sequence comparisons of the region surrounding glycine-142 indicated that it is highly conserved among lipases from different species, suggesting a crucial role of this domain for the LPL structure. Expression studies of the mutant LPL cDNA in COS-7 cells produced normal amounts of enzyme mass. However, the mutated LPL was not catalytically active, nor was it efficiently secreted from the cells. This established that the Gly----Glu substitution at amino acid 142 is sufficient to abolish enzymatic activity and to result in the chylomicronemia syndrome observed in these patients.