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Type I Hyperlipoproteinemia Due to a Novel Loss of Function Mutation of Lipoprotein Lipase, Cys²³⁹Trp, Associated with Recurrent Severe Pancreatitis

Department of Medicine IV (S.J., D.L., R.-M.S., K.R., H.-U.H., S.M.), University of Tübingen, 72076 Tübingen; and Department of Clinical Chemistry (M.M.H., W.M.), University of Freiburg, 79106 Freiburg, Germany

Address correspondence and requests for reprints to: Stephan Matthaei, M.D., Department of Medicine IV, University of Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: Stephan.Matthaei{at}med.uni-tuebingen.de

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 vitro assay. In postheparin plasma neither LPL mass nor activity was detectable, whereas hepatic lipase activity was normal. Direct sequencing of all 10 exons of the LPL gene revealed that the patient was homozygous for a hitherto unknown mutation in exon 6, Cys²³⁹Trp. The mutation prevents the formation of the second disulfide bridge of LPL, which is an essential part of the lid covering the catalytic center. Consequently, misfolded LPL is rapidly degraded within the cells, causing the absence of LPL immunoreactive protein in the plasma of this patient. In conclusion, we have identified a novel loss of function mutation in the LPL gene (Cys²³⁹Trp) of a patient with type I hyperlipoproteinemia suffering from severe recurrent pancreatitis. After initiation of heparin therapy (10,000 U/day sc), the patient experienced no more episodes of pancreatitis, although heparin therapy did not affect serum triglyceride levels.