Type I hyperlipoproteinemia due to a novel loss of function mutation of lipoprotein lipase, Cys(239)-> Trp, associated with recurrent severe pancreatitis

Lipoprotein lipase (LPL) is the major enzyme responsible for the hydrolysis of triglyceride-rich lipoproteins in plasma. The purpose of this study was to examine the molecular pathogenesis of type I hyperlipoproteinemia in a patient suffering from recurrent severe pancreatitis. Apolipoprotein (apo) CII concentration was normal as well as apo CII-activated LPL in an in vitr o assay. In postheparin plasma neither LPL mass nor activity was detectable , whereas hepatic lipase activity was normal. Direct sequencing of all 10 e xons of the LPL gene revealed that the patient was homozygous for a hithert o unknown mutation in exon 6, Cys(239)-->Trp. The mutation prevents the for mation of the second disulfide bridge of LPL, which is an essential part of the lid covering the catalytic center. Consequently, misfolded LPL is rapi dly degraded within the cells, causing the absence of LPL immunoreactive pr otein in the plasma of this patient. In conclusion, we have identified a no vel loss of function mutation in the LPL gene (Cys(239)-->Trp) Of. patient with type I hyperlipoproteinemia suffering from severe recurrent pancreatit is. After initiation of heparin therapy (10,000 U/day sc), the patient expe rienced no more episodes of pancreatitis, although heparin therapy did not affect serum triglyceride levels.