Abstract
Lipoprotein lipase (LPL) is a complex enzyme consisting of multiple functional domains essential for the initial hydrolysis of triglycerides present in plasma lipoproteins. Previous studies have localized the catalytic domain of LPL, responsible for the hydrolytic function of the enzyme, to the N-terminus whereas the C-terminal end may play a role in lipid and heparin binding. To date, most described missense mutations resulting in a nonfunctional LPL have been located in the N-terminal region of the enzyme. In this manuscript we describe the defect in the LPL gene of a patient with triglycerides ranging from normal to 12,000 mg/dl, low LPL mass, and no LPL activity in post-heparin plasma. Sequencing of patient PCR-amplified DNA identified two separate mutations in the C-terminal domain of LPL: an A-->T transversion at nucleotide 1484 resulting in a Glu410-->Val substitution and a C-->G mutation at position 1595 that introduces a premature stop codon at position 447. Digestion with MaeIII and MnII established that the patient is a true homozygote for both mutations. In order to investigate the functional significance of these defects, mutant enzymes containing either the Val410 or the Ter447 mutations as well as both Val410 and Ter447, were expressed in vitro. Compared to the wild-type enzyme, LPL447 demonstrated a moderate reduction of specific activity using triolein (70% of normal) and tributyrin (74% of normal) substrates, while LPL410 had a significant (11% and 23% of normal) reduction of the normal lipase and esterase specific activities, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Highlights
Lipoprotein lipase (LPL) is a complex enzyme consisting of multiple functional domains essential for the initial hydrolysis of triglycerides present in plasma lipoproteins
In this report we describe the molecular defect leading to a functional deficiency of LPL in a patient presenting with the familial chylomicronemia syndrome
LPL is a complex enzyme that consists of multiple functional domains required for activity
Summary
Lipoprotein lipase (LPL) is a complex enzyme consisting of multiple functional domains essential for the initial hydrolysis of triglycerides present in plasma lipoproteins. Most described missense mutations resulting in a nonfunctional LPL have been located in the N-terminal region of the enzyme. In this manuscript we describe the defect in the LPL gene of a patient with triglycerides ranging from normal to 12,000 mg/dl, low LPL mass, and no LPL activity in postheparin plasma. Despite its location in the C-terminal domain of LPL, this mutation does not directly disrupt the heparin-binding properties of the mutant enzyme or its ability to interact with or hydrolyze either lipid or water-soluble substrates. O u r studies indicate that, in addition to the proposed role in the lipid binding function, the C-terminal domain may play an important role in the formation of the active LPL dimer.-Previato, L., 0.Guardamagna, K.
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