A NOVEL AMINO-ACID SUBSTITUTION (HIS183-]GLN) IN EXON-5 OF THE LIPOPROTEIN-LIPASE GENE RESULTS IN LOSS OF CATALYTIC ACTIVITY - PHENOTYPIC-EXPRESSION OF THE MUTANT-GENE IN A HETEROZYGOUS STATE

We have identified a hitherto unrecognized mutation of the lipoprotein lipase gene (LPL) in a Finnish family with Russian and Swiss ancestor s. A single base pair substitution of a guanine for cytosine in codon 183 of exon 5 of the LPL gene results in a change of histidine to glut amine in the mature enzyme protein. Expression of a mutant cDNA constr uct in COS cells resulted in secretion of inactive LPL enzyme protein confirming the functional significance of the mutation. The proband, a 50-year-old female and her two daughters were all heterozygous for th e His183-->Gln mutation. Clinically, the proband was characterized by variable and occasionally severe hypertriglyceridemia, obesity, hypert ension, coronary heart disease and non-insulin-dependent diabetes mell itus. The daughters, aged 24 and 19 years, were also obese but had mil der hypertriglyceridemia. In conclusion, we have identified a novel LP L mutation that results in the synthesis of an inactive enzyme protein . Although the assessment of a causative link between the mutation and hyperlipidemia awaits further studies, our data suggest that heterozy gosity for a functional defect of LPL should be considered in patients presenting with the metabolic dyslipidemic syndrome, ''syndrome-X.'' -Tenkanen, H., M-R. Taskinen, M. Antikainen, I. Ulmanen, K. Kontula, a nd C. Ehnholm. A novel amino acid substitution (His183-->Gln) in exon 5 of the lipoprotein lipase gene results in loss of catalytic activity : phenotypic expression of the mutant gene in a heterozygous state.