Pseudodominance of lipoprotein lipase (LPL) deficiency due to a nonsense mutation (Tyr₃₀₂>Term) in exon 6 of LPL gene in an Italian family from Sardinia (LPL_Olbia)

Abstract

We analyzed the molecular defect in the lipoprotein lipase (LPL) gene of a young boy from Sardinia who had primary hyperchylomicronemia, pancreatitis, and a complete LPL deficiency in post-heparin plasma. Analysis of LPL gene was performed by using single strand conformation polymorphism (SSCP) and direct sequencing of SSCP-positive region. The proband was homozygous for a C > A transversion in exon 6, which converts the codon for tyrosine at position 302 into a termination codon and eliminates an RsaI restriction site; this allowed the rapid screening of the proband's family members, among whom nine heterozygotes and one additional homozygote were identified. The homozygote was the proband's paternal grandmother who had shown the first clinical manifestation (recurrent pancreatitis) of LPL deficiency at the age of 54 years. LPL mutation carriers showed a mild dyslipidemic phenotype characterized by a reduction of high density lipoprotein-cholesterol (HDL-C) levels, HDL-C/total cholesterol ratio, and low density lipoprotein (LDL) size, associated with a variable increase of triglyceride levels. Five of these carriers were also heterozygotes for beta-thalassemia (Q39X mutation). In these double mutation carriers, plasma HDL-C levels were higher and plasma triglycerides tended to be lower than in carriers of LPL mutation alone. The Tyr302 > Term mutation encodes a truncated protein of 301 amino acids that is probably not secreted by the LPL producing cells. This is the first mutation of LPL gene found in Sardinians.

Genetics of LDL particle heterogeneity

“…Carriers of this defective mutation had smaller LDL size compared with noncarrier family members (106). Similarly, lower LDL size was observed among carriers of the LPL Tyr302-Ter mutation in an Italian family (107). Hokanson et al (77) confirmed the LDL size-reducing effect of LPL deficiency in five families with structural mutations in the LPL gene.…”

Inherited Apolipoprotein A-V Deficiency in Severe Hypertriglyceridemia

“…26 This result suggests that other genetic/ environmental factors contribute to the elevation of plasma TG in heterozygotes for apoA-V deficiency as it occurs in heterozygotes for LPL deficiency in whom the level of fasting plasma TG may be in the normal range or slightly elevated, the latter in the case of subjects older than 50 or with some degree of adiposity. 16,27,28 In our kindred apoA-V mutation, carriers with plasma TG Ͼ1.70 mmol/L tended to be older (47.8Ϯ15.1 versus 28.4Ϯ15.1 years) and to have higher body mass index (ϩ7.5%) and plasma glucose (ϩ12%) than the mutation carriers with normal TG levels. The variability of plasma TG in apoA-V mutation carriers cannot be explained by some common polymorphisms of candidate genes (APOA5, APOC3, LPL, and APOE) affecting plasma TG levels (Table 1).…”

“…Maternal grandfather (II.3) had moderate mixed hyperlipidemia; paternal grandfather (II.1) and 2 siblings of proband's father (III.2 and III.5) had mild hypertriglyceridemia. The pretreatment level of plasma postheparin LPL activity of the proband (5.08Ϯ0.39 mol free fatty acid [FFA]/mL per hour, meanϮSD of triplicate determinations), assayed in vitro in the presence of control plasma, was below the lower limit of our reference range (8 to 15 mol FFA/mL per hour); 16 hepatic lipase activity was 40.4Ϯ2.3 mol FFA/mL per hour (reference range 35 to 55 mol FFA/mL per hour). A subsequent LPL assay performed with fresh postheparin plasma resulted in a value of 6.10Ϯ0.23 mol FFA/ mL per hour (Table 2).…”

“…15 Lipoprotein and hepatic lipase activities in postheparin plasma were assayed as previously reported. 16 In the first LPL assay, we used postheparin plasma that had been collected during the first clinical examination of the proband and had been stored at Ϫ80°C for some weeks. The second LPL assay was performed using freshly isolated postheparin plasma collected from the proband during -3 fatty acids treatment.…”

Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia

“…Among the 21 unrelated index cases, seven were carriers of novel variants (patients 2, 3,4,8,9,23,26) and three (patients 1, 20, 22) were carriers of two variants [p.(G81D) and p.(Y329* *)], reported previously by our group [15,16] (Table 1 and Supplemental tables S.4A, S.5, S.6 and S.7).…”