Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation.

Abstract

Familial lipoprotein lipase (LPL) deficiency is a rare genetic disorder accompanied by well-characterized manifestations. The phenotypic expression of heterozygous LPL deficiency has not been so clearly defined. We studied the pedigree of a proband known to be homozygous for a mutation resulting in nonfunctional LPL. Hybridization of DNA from 126 members with allele-specific probes detected 29 carriers of the mutant allele. Adipose tissue LPL activity, measured previously, was reduced by 50% in carriers, but did not reliably distinguish them from noncarriers. Carriers were prone to the expression of a form of familial hypertriglyceridemia characterized by increased plasma triglyceride, VLDL cholesterol and apolipoprotein B, and decreased LDL and HDL cholesterol concentrations. These manifestations were age modulated, with conspicuous differences between carriers and noncarriers observed only after age 40. Several noncarriers exhibited similar lipid abnormalities, but without the inverse relationship between VLDL cholesterol and LDL cholesterol noted among carriers. In addition to age and carrier status, the potentially reversible conditions, obesity, hyperinsulinemia and lipid-raising drug use were contributory. Thus heterozygous lipoprotein lipase deficiency, together with age-related influences, may account for a form of familial hypertriglyceridemia. (J. Clin. Invest.

A Pro12Ala polymorphism in the human peroxisome proliferator-activated receptor-gamma 2 is associated with combined hyperlipidaemia in obesity

“…LPL activity has also been shown to correlate strongly with plasma HDL levels (28). Similar alterations in blood lipid profile (increased triglycerides, decreased HDL) are seen in heterozygous LPL deficiency (29), an effect which is more pronounced in obese individuals (30). The effect of the Ala allele on blood lipid profile might only be revealed in the obese state due to the larger adipose tissue mass and therefore relative abundance of the fat-specific PPARg 2 isoform.…”

Interaction between variant apolipoproteins C-II and E that affects plasma lipoprotein concentrations.

“…10 - 14 The assessment of potentially interacting genetically determined factors, perhaps even apo E isoforms, may have further explained the phenotypic variability seen in that family. Others have observed in unrelated subjects that obligate carriers of defective LPL genes have biochemical features, such as a diminished LPL activity to LPL mass ratio that distinguished them from normal subjects.…”

“…12 Heterozygosity for a mutant LPL gene in combination with another factor may underlie hyperlipoproteinemia types IIB and/or IV. 1013 - 14 In one kindred with familial hypercholesterolemia (FH) due to an LDLR defect, a second factor, unidentified but segregating as a Mendelian dominant trait, obliterated the usually deleterious phenotypic effect of the mutant LDLR gene, with a resulting neutral lipoprotein phenotype. 15 Large kindreds are useful for identification of polygenic interactions that affect lipoprotein phenotypes.…”

Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol.

“…Perhaps this should not be surprising because individuals who are obligate heterozygotes for LPL deficiency and hence have only half-normal LPL activities often do not have elevated plasma TG levels 51 -52 ; on the other hand, Wilson et al 34 recently reported that most normotriglyceridemic heterozygotes for LPL deficiency do have low HDL levels. Presumably, in the presence of a moderate reduction of LPL activity, whether structural or functional in origin, other factors, ie, overproduction of VLDL triglycerides or defective VLDL particles, must be present before a patient develops definite hypertriglyceridemia.…”