Original Article
A Mutation in the Human Lipoprotein Lipase Gene as the Most Common Cause of Familial Chylomicronemia in French Canadians
N Engl J Med 1991; 324:1761-1766June 20, 1991
- Abstract
Background.
Lipoprotein lipase hydrolyzes the triglyceride core of chylomicrons and very-low-density lipoproteins and has a crucial role in regulating plasma lipoprotein levels. Deficiencies of lipoprotein lipase activity lead to aberrations in lipoprotein levels. Worldwide, the frequency of lipoprotein lipase deficiency is highest among French Canadians. We sought to determine the molecular basis of the disorder in this population.
Methods.
The entire coding sequence of the lipoprotein lipase gene from one French Canadian patient was amplified by the polymerase chain reaction and sequenced. Exon 5 from 36 other French Canadian patients was amplified and analyzed by dot blot hybridization with allele-specific oligonucleotides.
Results.
Sequence analysis revealed a missense substitution of leucine (CTG) for proline (CCG) at residue 207 in exon 5. This mutation was found on 54 of the 74 mutant alleles (73 percent) in the patients. Studies of site-directed in vitro mutagenesis have confirmed that this mutation generates inactive lipoprotein lipase and is the cause of lipoprotein lipase deficiency.
Conclusions.
We have identified a missense mutation at residue 207 of the lipoprotein lipase gene that is the most common cause of lipoprotein lipase deficiency in French Canadians. This mutation can be easily detected by dot blot analysis, providing opportunity for definitive DNA diagnosis of the disorder and identification of heterozygous carriers. (N Engl J Med 1991; 324:1761–6.)
Media in This Article
Figure 1
DNA Sequences of the Noncoding Strand from Exon 5 of a French Canadian Patient with Lipoprotein Lipase Deficiency and a Normal Control.Figure 2
Allele-Specific—Oligonucleotide Hybridization of Amplified Exon 5 DNA from Nine French Canadian Patients with Lipoprotein Lipase Deficiency.Article Activity
- Article
PATIENTS with inherited chylomicronemia usually have plasma triglyceride levels above 17 mmol per liter (1500 mg per deciliter) and high-density lipoprotein (HDL) levels of less than 0.52 mmol per liter (20 mg per deciliter) while fasting.1 They usually present in childhood with abdominal pain, recurrent attacks of pancreatitis, and eruptive xanthomas. In most cases, this disorder is inherited as an autosomal recessive trait and is due to catalytically defective lipoprotein lipase, the key enzyme involved in the hydrolysis of the triglyceride core of circulating chylomicrons and very-low-density lipoproteins (VLDLs). In the remainder of cases, the absence of lipoprotein lipase activity may be due to the absence of or an abnormality in apolipoprotein C-II,2 the cofactor required for the activation of lipoprotein lipase, or to the presence of a circulating inhibitor.3
The frequency of carriers of lipoprotein lipase deficiency is estimated to be 1 in 500 in the general population.1 The highest reported frequency of the disorder worldwide occurs in certain areas of Quebec in Canada, where the carrier rate is approximately 1 in 40.4
Human lipoprotein lipase is active as a homodimer5 that is bound to the heparan sulfate side chains of glycoproteins located on the surface of the vascular and capillary endothelium of extrahepatic tissues.6 , 7 Human lipoprotein lipase complementary DNA (cDNA) has been cloned and sequenced8 and is located on the short arm of chromosome 8,9 where it consists of 10 exons10 spanning approximately 30 kilobases. Numerous alterations of the DNA sequence have been reported to cause lipoprotein lipase deficiency. These include large rearrangements of DNA,11 , 12 but the majority are single-base substitutions generating missense and nonsense mutations in exons 4, 5, and 6.13 14 15 16 17 18 19 20 In most instances, these mutations in the lipoprotein lipase gene differ among unrelated families and among population groups.
We report a missense mutation that results in the substitution of leucine for proline at amino acid 207 and that was found on 54 of the 74 mutant alleles (73 percent) in 37 apparently unrelated French Canadian patients with lipoprotein lipase deficiency. This mutation can easily be detected by means of the polymerase chain reaction followed by dot blot hybridization analysis with allele-specific oligonucleotides. These simple and reliable methods allow definitive DNA diagnosis of lipoprotein lipase deficiency and identification of heterozygous carriers, and will be useful for genetic counseling and studies of phenotypic expression.
Methods
Subjects
We examined a total of 37 French Canadian probands with lipoprotein lipase deficiency in this study. No genetic relationship was found between any of them for a minimum of three generations and, in all instances, as far back as could be ascertained. Also included for comparison were 34 other, unrelated probands with the disorder who were of different non-French Canadian ancestries.
To ascertain the frequency of the Pro→Leu207 mutation among persons attending lipid clinics, blood samples were collected from 180 unrelated, consecutively selected French Canadian patients of these clinics. Also included for comparative purposes were 170 control subjects of the same ancestry who had normolipidemia.
Lipoprotein Lipase Mass and Activity
Blood samples were collected from all patients after an overnight fast. Total cholesterol, triglycerides, and HDL and low-density lipoprotein (LDL) cholesterol were measured according to protocols previously described.4 , 20 Blood samples were also obtained after the administration of heparin; lipoprotein lipase mass and activity were measured in plasma from both sets of blood samples, in COS-1 cell medium, and in cell-homogenate samples, as previously described.21
DNA Analysis
Genomic DNA was isolated from the white cells of all probands and some of their family members.22 DNA haplotypes of mutant lipoprotein lipase alleles were constructed with use of the HindIII, BamHI, and PvvII23 , 24 restriction-fragmentlength polymorphisms at the lipoprotein lipase—gene locus.
A French Canadian proband deficient in lipoprotein lipase activity and homozygous for the most frequent lipoprotein lipase—gene haplotype H2 (HindIII +, BamHI —, PraII+) for which no mutation had been detected was selected for the sequence analysis. Each of the 10 exons encoding the amino acid sequence of lipoprotein lipase was individually amplified from 0.5 to 1 fig of genomic DNA with the polymerase chain reaction as previously described.19 The amplified exons were then purified and sequenced either directly or after cloning into a pUC18 vector.
Oligonucleotide Hybridization of Amplified DNA
Exon 5 of the lipoprotein lipase gene from all probands and controls was amplified by polymerase chain reaction, and approximately 50 ng of the DNA was denatured and transferred in duplicate onto nylon membranes (Hybond N-plus, Amersham). Oligonucleotides homologous to the normal and mutant sequences spanning the Pro→Leu207 substitution were synthesized on an automated DNA synthesizer (model 380A, Applied Biosystems) and end-labeled with [r-32P]ATP. Oligonucleotide hybridization was performed as previously described,19 , 20 with the following modifications. Hybridization was performed in a buffer containing 1 percent bovine serum albumin, 0.5 mol of sodium phosphate per liter (pH 7.2), 1 mmol of EDTA per liter (pH 8.0), and 7 percent sodium dodecyl sulfate, in which each oligonucleotide at 1 × 106 counts per minute per milliliter was incubated for two hours at 48°C. Filters were washed in several buffers under the following conditions: in buffer 1 (2 × SSPE, 0.5 percent sodium dodecyl sulfate) for 5 minutes at room temperature, in buffer 2 (1 × SSPE, 0.25 percent sodium dodecyl sulfate) for 15 minutes at room temperature, and in buffer 3 (0.1 × SSPE and 0.1 percent sodium dodecyl sulfate) for 30 minutes at 42°C for the mutant oligonucleotide and at 43°C for the wild-type probe (1 × SSPE denotes 150 mM sodium chloride, 10 mM sodium phosphate, and 1 mM EDTA).
Site-Directed Mutagenesis of Lipoprotein Lipase cDNA
A cDNA fragment encompassing the entire coding sequence (nucleotides 61 to 1642), flanked by 113 bp (base pairs) 5′ to the initiation codon and 40 bp 3′ to the termination codon, was prepared from the full-length lipoprotein lipase cDNA clone (pLPL35). This fragment was cloned into the Bluescript KSII+ vector (Stratagene), reexcised, and ligated into the phagemid vector CDM8,25 which served as a dual-function vector for both mutagenesis and expression. In vitro mutagenesis was performed according to a modified gapped-duplex DNA method. The template DNA for mutagenesis was prepared by annealing linearized and denatured CDM8 vector DNA with single-stranded CDM8—lipoprotein lipase template DNA. The end product is a double-stranded DNA template containing a single-stranded lipoprotein lipase cDNA gap for mutagenesis. This gapped-duplex DNA was annealed with a 17nucleotide mutagenic primer (5′CATTTACCTGAATGGAG3′) and filled with T4 DNA polymerase (Pharmacia). Mutant clones were identified by oligonucleotide hybridization and verified by DNA sequencing.
Transient Expression in COS-1 Cells
Expression phagemids were introduced into the COS-1 cells by electroporation as described elsewhere.19 (COS-1 [CV-1, origin of SV40] is a permissive cell line derived by transformation of simian CV-1 cells with an origin-defective SV40 genome.) The transfected cells were plated in 100-mm dishes, each holding 10 ml of medium containing 40 fig of heparin per milliliter, and incubated for 48 hours. After a change of medium and further incubation for 12 hours, the culture medium was removed, snap-frozen in 1-ml aliquots, and stored at — 70°C. The cells were counted and collected for the isolation of RNA and for the preparation of cell homogenates.
Results
DNA Analysis
We were able to construct DNA haplotypes for the mutant alleles in 22 of the 37 French Canadian patients with lipoprotein lipase deficiency (Table 1Table 1
Lipoprotein Lipase-Gene Haplotypes Associated with DNA Mutations in 22 French Canadian Probands with Lipoprotein Lipase Deficiency.). The majority of these patients proved to be homozygous for haplotype H2. Sequence analysis of exon 5 from one of these subjects revealed homozygosity for a C-to-T transition at nucleotide 875 of the published lipoprotein lipase cDNA sequence (Fig. 1Figure 1DNA Sequences of the Noncoding Strand from Exon 5 of a French Canadian Patient with Lipoprotein Lipase Deficiency and a Normal Control.). This mutation results in the amino acid substitution of leucine (CTG) for proline (CCG) at residue 207. Both the coding and noncoding strands of exon 5 DNA from several independent polymerase chain reactions were sequenced to confirm the presence of the Pro→Leu207 mutation. No other DNA alteration was detected in exon 5, and the DNA sequence of the nine remaining exons and the exon-intron junctions of the lipoprotein lipase gene were found to be normal. Since this single-base mutation does not alter a restriction site, it was assessed in other patients by means of allele-specific—oligonucleotide hybridization analysis.Haplotype H1 has previously been shown to be associated with a mutation at residue 188 of the lipoprotein lipase protein, which results in a substitution of glutamic acid for glycine. This mutation can be detected by polymerase chain reaction and restriction digestion with AvaII or by allele-specific—oligonucleotide hybridization. 15 , 16 The mutation was found on 13 of the 14 alleles with haplotype H1 (Table 1). There were four alleles from the French Canadian patients that did not carry either the Gly→Glu188 or the Pro→Leu207 mutation. These alleles with unknown mutations were associated with H1 and H2 haplo-types, and it is therefore likely that there are at least two additional rare mutations underlying lipoprotein lipase deficiency in this group of French Canadian patients.
Frequency of Pro→Leu207 Mutation on Dot Blot Hybridization Analysis
To determine the frequency of the mutation at residue 207 identified in the French Canadian and other patients with lipoprotein lipase deficiency, we used the polymerase chain reaction to amplify exon 5 of the lipoprotein lipase gene and carried out dot blot hybridization with allele-specific oligonucleotides. The sequence of the oligonucleotide probe specific for the normal allele was 5′CATTTACCCGAATGGAG3′, and that of the probe specific for the mutant allele was 5′CATTTACCTGAATGGAG3′. Autoradiography (Fig. 2Figure 2
Allele-Specific—Oligonucleotide Hybridization of Amplified Exon 5 DNA from Nine French Canadian Patients with Lipoprotein Lipase Deficiency.) clearly identified the patients homozygous or heterozygous for the Pro→Leu207 substitution. The results of the analysis of 71 probands are summarized in Table 2Table 2
Frequency of the Mutations Gly→Glu188 and Pro→Leu207 among 71 Probands with Lipoprotein Lipase Deficiency, According to Origin.. Among the 37 French Canadian patients (74 alleles), the Pro→Leu207 mutation occurred on 54 alleles (73 percent), and the Gly→Glu188 mutation on 16 alleles (22 percent). In total, we identified the mutations on 70 of the 74 mutant lipoprotein lipase alleles (95 percent) in this group of French Canadian patients.The same experiments were also performed on DNA samples from 34 unrelated patients of 21 different ancestries other than French Canadian. Only one allele of a patient living in Germany was found to have the Pro→Leu207 mutation (Table 2). The details of the ancestry of this patient could not be established.
Dot blot hybridizations and restriction-fragment analyses were also performed to determine the frequencies of the Pro→Leu207 and Gly→Glu188 mutations among French Canadian control subjects with hyperlipidemia or normolipidemia. Eleven of 180 controls with hyperlipidemia were found to be heterozygous for the Pro→Leu207 mutation, but this mutation was not found among the 170 controls with normolipidemia. No control carried the Gly→Glu188 mutation.
In Vitro Mutagenesis and Expression
Phagemid DNA from one normal clone containing wild-type lipoprotein lipase cDNA (positive control), two mutant clones carrying the Pro→Leu207 mutation, and the vector clone (negative control) were purified and used to transfect COS-1 cells. As shown in Figure 3Figure 3
Autoradiograph of a Northern Blot of 10 μg of Total mRNA from COS-1 Cells Transfected with Different cDNAs., lipoprotein lipase messenger RNA (mRNA) (a 2.4-kilobase transcript) was present at similar levels in cells transfected with the normal and the mutant cDNA. There was no detectable lipoprotein lipase mRNA in COS-1 cells transfected with the vector alone, indicating that the endogenous expression of lipoprotein lipase by COS-1 cells was very limited.Lipoprotein lipase mass and activity were assayed in the medium of transfected COS-1 cells and in cell homogenates for both normal and mutant cDNA. Lipoprotein lipase protein was present in the medium of the cells transfected with the mutant cDNA, at 28 percent of the level in the normal control (Fig. 4Figure 4
Lipoprotein Lipase Mass (Panel A) and Activity (Panel B) in the 12-Hour Culture Medium (Solid Bars) and Cell Homogenate (Hatched Bars) of COS-1 Cells Transfected with the Normal Lipoprotein Lipase cDNA and the Mutant Pro→Leu207 cDNA.A). However, similar levels of lipoprotein lipase mass were detected in both the normal and the mutant cell homogenate. The enzymatic activity of the expressed mutant lipoprotein lipase in the medium was close to zero, as compared with the normal activity of the expressed wild-type lipoprotein lipase (Fig. 4B). These data demonstrate that the secreted mutant enzyme is catalytically inactive.Discussion
Worldwide, lipoprotein lipase deficiency occurs with the highest reported frequency in French Canadians, among whom the predicted carrier rate is 1 in 40 in certain regions of Quebec.4 We report a missense mutation in the human lipoprotein lipase gene that results in the substitution of leucine for proline at residue 207 of the mature protein and that was found on 54 of 74 mutant alleles (73 percent) in 37 unselected French Canadian patients with lipoprotein lipase deficiency. We have shown by studies of site-directed in vitro mutagenesis that this substitution produces a catalytically inactive lipoprotein lipase protein and is the cause of the lipoprotein lipase deficiency in these patients.
The mutagenesis studies showed that the levels of mutant and wild-type lipoprotein lipase mRNA in transfected COS-1 cells are similar, as are the levels of cell-associated lipoprotein lipase mass. This suggests that the Pro→Leu207 substitution has no major effect on the expression of the lipoprotein lipase gene. However, the substantial decrease in the mass levels of the mutant enzyme in culture medium either reflects decreased secretion of this form of lipoprotein lipase or indicates that it is less stable and has undergone rapid degradation. This may reflect the situation in vivo, since patients homozygous for the Pro→Leu207 mutation who are given heparin have an incremental increase in lipoprotein lipase mass that is lower than that in normal persons.
One of the longest conserved regions that shows complete residue identity in lipoprotein lipase from humans, cows, mice, and guinea pigs spans residues 178 to 210 of the enzyme in humans and is encoded by exon 5. The majority of the single-nucleotide substitutions in the lipoprotein lipase gene causing deficiency of the enzyme have been found in exon 5. The finding of another mutation in exon 5 clearly demonstrates the structural and functional importance of residues encoded by this exon.
The majority of the 5 million French Canadians now living in the province of Quebec are descendants of approximately 8500 settlers who migrated from Brittany, Normandy, and the western provinces of France between 1608 and 1763.26 Subsequent expansion of the gene pool due to the arrival of other immigrants has been limited. Because of the relative social and linguistic isolation, the present French Canadian population is mostly descended from the founding settlers. We have previously hypothesized that the high frequency of lipoprotein lipase deficiency among French Canadians is the result of mutations in the lipoprotein lipase gene in one or more of the founding settlers. Preliminary analysis has suggested that these mutations were introduced into the province of Quebec by French immigrants in the 17th and 18th centuries, and studies of the origin of the patients have revealed that the region of Perche, between Paris and Normandy, is the likely center of diffusion of a major mutation in the lipoprotein lipase gene in this population.27 A common origin is supported by the observation that all lipoprotein lipase alleles with the Pro→Leu207 mutation have the same haplotype. This is consistent with previous studies of human genetic diseases, which have revealed that specific mutations are often associated with only one haplotype and may represent an event in a single ancestor. Ultimate confirmation of the founder effect will depend on the detection of the Pro→Leu207 mutation in the peoples of France who share ancestors with the French Canadian patients.
The Pro→Leu207 mutation was detected in 11 heterozygotes (6.1 percent) among 180 randomly selected patients attending lipid clinics, but not in any of the 170 normolipidemic persons attending genetic clinics for other reasons. This suggests that the Pro→Leu207 substitution might be overrepresented among French Canadian patients with hyperlipidemia and might indicate that decreased lipoprotein lipase levels in carriers may contribute to the development of hyperlipidemia in these patients.21 This mutation can easily be detected by dot blot analysis. If the high frequency of this mutation can be confirmed in an independent group of French Canadians with hyperlipidemia, screening of selected patients in this population might become feasible.
Lipoprotein lipase has a pivotal role in the hydrolysis of triglycerides in plasma lipoproteins. This process initiates the conversion of chylomicrons and VLDLs to their remnant particles and also has a major modulating effect on the levels and lipid composition of HDLs and LDLs. An inverse correlation between HDL levels and coronary artery disease has previously been demonstrated.28 Levels of HDL show positive correlation with lipoprotein lipase activity.29 Probands who have complete deficiency of lipoprotein lipase activity have very low HDL levels but also have decreased LDL levels because of decreased conversion of VLDL to LDL, and these patients do not appear to be at an increased risk of premature atherosclerosis. Persons who are heterozygous for lipoprotein lipase deficiency have significantly reduced HDL cholesterol levels (P<0.01)21 , 30 and may have variable expression of hyperlipidemia that might predispose them to premature atherosclerosis.21 From a practical point of view, the discovery of the Pro→Leu207 mutation provides a unique opportunity for the identification of large numbers of carriers in the French Canadian population, which will enable us to examine the association between carrier status for lipoprotein lipase deficiency and the presence of premature atherosclerosis and hyperlipidemia.
Supported by grants from the Medical Research Councils of Canada and South Africa, the Canadian Heart Foundation, the Canadian Genetic Disease Network, and the National Institutes of Health (DK-02456). Dr. Ma is a postdoctoral fellow supported by the Medical Research Council of Canada, Dr. Julien is a Career Scientist of the Fonds de la Recherche en Santé du Québec, and Dr. Hayden is an Established Investigator of the British Columbia Children's Hospital.
We are indebted to Dr. Richard Lawn for the gift of the lipoprotein lipase cDNA clone and to Dr. Xingbo Wang for providing helpful suggestions on mutagenesis; to Elizabeth Cramb, Martha Kimura, and Steve Hashimoto for excellent technical assistance; and to David Kowbel for helpful suggestions on Northern blot analysis.
Source Information
From the Department of Medical Genetics, University of British Columbia, Vancouver (Y.M., H.E.H., M.V.M., L.A.C., M.R.H); the Department of Biochemistry (M.R.V.M., T.N.) and the Lipid Research Centre (P.J., C.G., P.J.L.), Laval University, Quebec; Hôpital Sainte-Justine, Université de Montreal, Montreal (M.L.); Clinical Research Institute of Montreal, Montreal (G.R., J.D.); and the Department of Medicine, University of Washington, Seattle (J.B.). Address reprint requests to Dr. Hayden at the Department of Medical Genetics, F168 University Hospital, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada.
- References
References
1
Nikkilä EA. Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, eds. The metabolic basis of inherited disease. 5th ed. New York: McGraw-Hill, 1983:622–42.
2
Breckenridge
Full Text | Web of Science | Medline3
Brunzell
Web of Science | Medline4
Gagne
Web of Science5
Brunzell JD. Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. Vol. 1. New York: McGraw-Hill. 1989:1165–80.
6
Cheng
Web of Science | Medline7
Cupp
Web of Science | Medline8
Wion
CrossRef | Web of Science | Medline9
Sparkes
CrossRef | Medline10
Deeb
CrossRef | MedlineErratum, Biochemistry 1989; 28:6786.
CrossRef | Web of Science11
Devlin
Web of Science | Medline12
Langlois
CrossRef | Web of Science | Medline13
Ameis
CrossRef | Web of Science | Medline14
Beg
CrossRef | Web of Science | Medline15
Emi
Web of Science | Medline16
Monsalve
CrossRef | Web of Science | Medline17
Emi
Web of Science | Medline18
Hata
Web of Science | Medline19
Henderson
CrossRef | Web of Science | Medline20
Henderson
Medline21
Babirak
CrossRef | Medline22
Mullenbach
Web of Science | Medline23
Fisher
CrossRef | Web of Science | Medline24
Funke
CrossRef | Web of Science | Medline25
Wang
CrossRef | Medline26
Charbonneau H, Robert N. Origines francaises de la population canadienne, 1608–1759. In: L'atlas historique du Canada. Vol. 1. Des origines a 1800. Montreal: Université de Montreal, 1987:118–9.
27
De Braekeleer
Web of Science28
Gordon
CrossRef | Web of Science | Medline29
Patsch
CrossRef | Web of Science | Medline30
Wilson
CrossRef | Web of Science | Medline
- Citing Articles (27)
Citing Articles
1
Eric W. Schaefer, Alicia Leung, Jelena Kravarusic, Neil J. Stone. (2011) Management of severe hypertriglyceridemia in the hospital: A review. Journal of Hospital Medicinen/a-n/a
CrossRef2
Schohraya Spahis, Michel Vanasse, Stacey A. Bélanger, Parviz Ghadirian, Emilie Grenier, Emile Levy. (2008) Lipid profile, fatty acid composition and pro- and anti-oxidant status in pediatric patients with attention-deficit/hyperactivity disorder. Prostaglandins, Leukotrienes and Essential Fatty Acids 79:1-2, 47-53
CrossRef3
Christophe Garenc, Samuel Aubert, Jerôme Laroche, Jean Bergeron, Claude Gagné, François Rousseau, Pierre Julien. (2006) Gene polymorphisms in the Quebec population: A risk to develop hypertriglyceridemia. Biochemical and Biophysical Research Communications 344:2, 588-596
CrossRef4
Kaspar Truninger, Peter A. Schmid, Michael M. Hoffmann, Philipp Bertschinger, Rudolf W. Ammann. (2006) Recurrent Acute and Chronic Pancreatitis in Two Brothers With Familial Chylomicronemia Syndrome. Pancreas 32:2, 215-219
CrossRef5
Philippa J. Talmud, Jeffrey W. Stephens. (2004) Lipoprotein lipase gene variants and the effect of environmental factors on cardiovascular disease risk. Diabetes, Obesity and Metabolism 6:1, 1-7
CrossRef6
Tjin-Shing Jap, Shwu-Fen Jenq, Yi-Chi Wu, Chih-Yang Chiu, Hon-Mei Cheng. (2003) Mutations in the Lipoprotein Lipase Gene as a Cause of Hypertriglyceridemia and Pancreatitis in Taiwan. Pancreas 27:2, 122-126
CrossRef7
Philippa J. Talmud. (2001) Genetic determinants of plasma triglycerides: Impact of rare and common mutations. Current Atherosclerosis Reports 3:3, 191-199
CrossRef8
Brigitte Gilbert, Mustapha Rouis, Sabine Griglio, Lionel de Lumley, Paul-Michel Laplaud. (2001) Lipoprotein lipase (LPL) deficiency: a new patient homozygote for the preponderant mutation Gly188Glu in the human LPL gene and review of reported mutations: 75 % are clustered in exons 5 and 6. Annales de Génétique 44:1, 25-32
CrossRef9
Siegmund Gehrisch. (1999) Common mutations of the lipoprotein lipase gene and their clinical significance. Current Atherosclerosis Reports 1:1, 70-78
CrossRef10
Silvia Santamarina-Fojo. (1998) THE FAMILIAL CHYLOMICRONEMIA SYNDROME. Endocrinology & Metabolism Clinics of North America 27:3, 551-567
CrossRef11
Jean Davignon, Jacques Genest. (1998) GENETICS OF LIPOPROTEIN DISORDERS. Endocrinology & Metabolism Clinics of North America 27:3, 521-550
CrossRef12
Chi-Pui Pang. (1998) Molecular Diagnostics for Cardiovascular Disease. Clinical Chemistry and Laboratory Medicine 36:8, 605-614
CrossRef13
Andrew G. Clark, Kenneth M. Weiss, Deborah A. Nickerson, Scott L. Taylor, Anne Buchanan, Jari Stengård, Veikko Salomaa, Erkki Vartiainen, Markus Perola, Eric Boerwinkle, Charles F. Sing. (1998) Haplotype Structure and Population Genetic Inferences from Nucleotide-Sequence Variation in Human Lipoprotein Lipase. The American Journal of Human Genetics 63:2, 595-612
CrossRef14
Pierre Julien, Claude Gagné, M.R. Ven Murthy, Georges Lévesque, Sital Moorjani, François Cadelis, Michael R. Hayden, Paul J. Lupien. (1998) Dyslipidemias associated with heterozygous lipoprotein lipase mutations in the French-Canadian population. Human Mutation 11:S1, S148-S153
CrossRef15
Rachel M Fisher, Steve E Humphries, Philippa J Talmud. (1997) Common variation in the lipoprotein lipase gene: effects on plasma lipids and risk of atherosclerosis. Atherosclerosis 135:2, 145-159
CrossRef16
Luc Foubert, Taco Bruin, Jean Luc De Gennes, Ewa Ehrenborg, Jean Furioli, John Kastelein, Pascale Benlian, Michael Hayden. (1997) A single Ser259Arg mutation in the gene for lipoprotein lipase causes chylomicronemia in Moroccans of Berber ancestry. Human Mutation 10:3, 179-185
CrossRef17
France Mailly, Jutta Palmen, David P. R. Muller, Tracy Gibbs, June Lloyd, John Brunzell, Paul Durrington, Kostas Mitropoulos, John Betteridge, Gerald Watts, Hans Lithell, Franco Angelico, Steve E. Humphries, Philippa J. Talmud. (1997) Familial lipoprotein lipase (LPL) deficiency: A catalogue of LPL gene mutations identified in 20 patients from the UK, Sweden, and Italy. Human Mutation 10:6, 465-473
CrossRef18
T. W. A. DE BRUIN, F. MAILLY, H. H. J. J. VAN BARLINGEN, R. FISHER, M. CASTRO CABEZAS, P. TALMUD, G. M. DALLINGA-THIE, S. E. HUMPHRIES. (1996) Lipoprotein lipase gene mutations D9N and N291S in four pedigrees with familial combined hyperlipidaemia. European Journal of Clinical Investigation 26:8, 631-639
CrossRef19
D. Matern, H. Seydewitz, H. Niederhoff, H. Wiebusch, M. Brandis. (1996) Dyslipidaemia in a boy with recurrent abdominal pain, hypersalivation and decreased lipoprotein lipase activity. European Journal of Pediatrics 155:8, 660-664
CrossRef20
Ven Murthy, Pierre Julien, Claude Gagné. (1996) Molecular pathobiology of the human lipoprotein lipase gene. Pharmacology & Therapeutics 70:2, 101-135
CrossRef21
Manuel Júdice Halpern. (1995) Lipids and atherosclerosis. Molecular Aspects of Medicine 16:6, 509-710
CrossRef22
Yuanhong Ma, Ming-Sun Liu, David Chitayat, Taco Bruin, Ulrike Beisiegel, Pascale Benlian, Luc Foubert, Jean Luc De Gennes, Harald Funke, Ian Forsythe, Shirley Blaichman, Maria Papanikolaou, D. W. Erkelens, John Kastelein, John D. Brunzell, Michael R. Hayden. (1994) Recurrent missense mutations at the first and second base of codon Arg243 in human lipoprotein lipase in patients of different ancestries. Human Mutation 3:1, 52-58
CrossRef23
Steve E. Humphries. (1993) The application of molecular biology techniques to the diagnosis of hyperlipidaemia and other risk factors for cardiovascular disease. Clinica Chimica Acta 216:1-2, S5-S18
CrossRef24
A. Zambon, J.D. Brunzell, A. Torres, C. Gagne, S. Moorjani, P.J. Lupien, M.R. Hayden, S. Bijvoet. (1993) Prevention of raised low-density lipoprotein cholesterol in a patient with familial hypercholesterolaemia and lipoprotein lipase deficiency. The Lancet 341:8853, 1119-1121
CrossRef25
Yuanhong Ma, Bonnie I. Wilson, Saskia Bijvoet, Howard E. Henderson, Elizabeth Cramb, Ghislaine Roederer, M.R. Ven Murthy, Pierre Julien, Henk D. Bakker, John J.P. Kastelein, John D. Brunzell, Michael R. Hayden. (1992) A missense mutation (Asp250→Asn) in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries. Genomics 13:3, 649-653
CrossRef26
S. S. FOJO, H. B. BREWER. (1992) Hypertriglyceridaemia due to genetic defects in lipoprotein lipase and apolipoprotein C-II. Journal of Internal Medicine 231:6, 669-677
CrossRef27
Kimmo Kontula, Ulla-Maija Koivisto, Helena Miettinen. (1992) The Use of PCR in Diagnosing Lipoprotein Disorders. Annals of Medicine 24:3, 195-199
CrossRef
