Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.

Abstract

The DNA sequences were determined for the lipoprotein lipase (LPL) gene from five unrelated Japanese patients with familial LPL deficiency. The results demonstrated that all five patients are homozygotes for distinct point mutations dispersed throughout the LPL gene. Patient 1 has a G-to-A transition at the first nucleotide of intron 2, which abolishes normal splicing.Patient 2 has a nonsense mutation in exon 3 (Tyr" -> Stop) and patient 3 in exon 8 (Trp"2 --Stop). The latter mutation emphasizes the importance of the carboxy-terminal portion of the enzyme in the expression of LPL activity. Missense mutations were identified in patient 4 (Asp2'-Glu) and patient 5 (Arg'3 His) in the strictly conserved amino acids. Expression study of both mutant genes in COS-1 cells produced inactive enzymes, establishing the functional significance of the two missense mutations. In these patients, postheparin plasma LPL mass was either virtually absent (patients 1 and 2) or significantly decreased (patients 3-5). To detect these mutations more easily, we developed a rapid diagnostic test for each mutation. We also determined the DNA haplotypes for patients and confirmed the occurrence of multiple mutations on the chromosomes with an identical haplotype. These results demonstrate that familial LPL deficiency is a heterogeneous genetic disease caused by a wide variety of gene mutations. (J. Clin. Invest.

Diagnosis and Management of Type I and Type V Hyperlipoproteinemia

“…In particular, as nonsense mutations in exon 3 (Y61X) and exon 8 (W382X) 27) and a single-base deletion in exon 5 (A221Ter (del 1bp)) 28) have been identified in multiple families of Japanese patients, these mutations are considered to be distributed relatively widely in the LPL gene of Japanese. On the other hand, S447X, which is considered to be a gain-offunction polymorphism, has been shown to reduce TG and increase HDL-cholesterol 29) .…”

Genotype-phenotype studies of six novelLPL mutations in Chinese patients with hypertriglyceridemia

“…Genomic DNA extracted from whole blood was amplified by PCR using described primers of the promoter, 10 exons and the intron-exon boundaries of the LPL gene (Monsalve et al, 1990;Gotoda et al, 1991;Yang et al, 1995). The 10 µL PCR mixture contained 50 ng DNA, 10 pmol of each primer, 0.1 mM dNTP, 0.2 µL 3000 µCi/mmol α-32 P dCTP (Amersham Biosciences, Bucks, UK), 1.5 mM magnesium chloride, 0.2 U Taq polymerase (Gibco BRL, Gaithersburg, MD), 10% polyoxethylene ether (Sigma, St Louis, MO).…”

Lipoprotein Lipase Deficiency (R243H) in a Type 2 Diabetes Patient with Multiple Arterial Aneurysms

“…She had hypertension and type 2 diabetes mellitus (T2DM), both of which had been well controlled since initially being diagnosed. To the best of our knowledge, only two cases with this homozygous missense mutation have been reported, but these patients were too young (23 days and 2 months after birth) for an evaluation of atherosclerosis (6,9). Notably, our present case had developed multiple arterial aneurysms and several atherosclerotic lesions in the coronary and carotid arteries, suggesting that this mutation may thus play a role in atherosclerotic progression.…”

“…Consistently, COS-1 cells expressing R243H-mutated LPL reportedly secrete the mutated LPL protein (9). It has been proposed that LPL protein lacking any lipase activity may function as a bridge between apoB-containing lipoproteins and proteoglycans on vessel walls, thereby retaining atherogenic lipoproteins on endothelial cells, and leading to the progression of atherosclerosis (7,14).…”