A Mutation in the Human Lipoprotein Lipase Gene as the Most Common Cause of Familial Chylomicronemia in French Canadians

Ma, Yuanhong; Henderson, Howard; Murthy, M.R.V.; Roederer, Ghislaine O.; Monsalve, María Victoria; Clarke, Lorne; Normand, Thierry; Julien, Pierre; Gagné, Claude; Lambert, Marie; Davignon, Jean; Lupien, Paul J.; Brunzell, John D.; Hayden, Michael R.

doi:10.1056/nejm199106203242502

Cited by 96 publications

(44 citation statements)

References 21 publications

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“…Among the numerous mutations responsible for primary LPL deficiency, three missence mutations of the LPL gene (G188E, P207L, D250N) are particularly frequent in the Saguenay-Lac-St-Jean region in the province of Québec in Canada. [10][11][12] The P207L mutation is associated with a carrier frequency of approximately 2% in this population. 13 Heterozygotes carrying these mutations in the LPL gene usually show a deteriorated lipid profile that includes elevated plasma TG levels and decreased HDL cholesterol concentrations.…”

Section: Introductionmentioning

confidence: 99%

Effect of obesity on HDL and LDL particle sizes in carriers of the null P207L or defective D9N mutation in the lipoprotein lipase gene: the Québec LipD Study

et al. 2003

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BACKGROUND:We have recently demonstrated that French Canadians bearing a mutation in the lipoprotein lipase (LPL) gene present an impaired lipoprotein-lipid profile characterized by small low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles compared with healthy subjects. It has also been documented that obesity has a significant impact on HDL and LDL particle sizes. OBJECTIVE: To examine the extent to which obesity modulates HDL and LDL particle sizes among carriers of mutations in the LPL gene. SUBJECTS: Analyses were carried out in 206 heterozygous carriers of the D9N mutation (N ¼ 118) or the P207L mutation (N ¼ 88). MEASUREMENTS: Lipoprotein particle sizes were measured on whole plasma by nondenaturing polyacrylamide gradient gel electrophoresis. RESULTS: In general, body mass index (BMI) and waist circumference were significant correlates of LDL and HDL particle sizes among heterozygous carriers of the P207L or D9N mutation in the LPL gene, with relatively similar associations among men and women. Multivariate analyses indicated that variations in waist circumference but not BMI were an independent predictor of variations in both HDL particle size (5.2%, P ¼ 0.0005) and LDL particle size (5.9%, P ¼ 0.01) in the entire group of heterozygotes for LPL mutation in a model that included the nature of the LPL mutation (D9N vs P207L), gender, age, cholesterol and plasma TG levels. Interestingly, there was a significant interaction between plasma TG levels and waist circumference or BMI in modulating HDL particle size. Indeed, an increased waist circumference or BMI was associated with a significant reduction in HDL particle size among subjects with plasma TG levels r3.5 mmol/l, but not among those with marked hypertriglyceridemia (TG levels 43.5 mmol/l). CONCLUSION: These results suggest that abdominal obesity, more so that overall obesity, is an important determinant of variations in LDL and HDL particle size among heterozygous carriers of mutations in the LPL gene, perhaps further contributing to modulate the risk of CHD in these individuals.

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Section: Introductionmentioning

confidence: 99%

Effect of obesity on HDL and LDL particle sizes in carriers of the null P207L or defective D9N mutation in the lipoprotein lipase gene: the Québec LipD Study

et al. 2003

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“…The French-Canadian population, which is primarily and historically located in the province of Quebec, has the highest prevalence worldwide of lipoprotein lipase deficiency. It includes a large pool of individuals at risk for atherosclerosis and other lipid-related diseases (22,23). These abnormalities are presumably related to a founder effect among the 8,000 ancestors of present-day French-Canadians, who have had relatively little cross-breeding with individuals from other national origin groups (24).…”

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confidence: 99%

Intestinal fatty acid binding protein and microsomal triglyceride transfer protein polymorphisms in French-Canadian youth

Stan

Lambert

Delvin

et al. 2005

Journal of Lipid Research

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“…Two different mutations at the f3-globin locus (3-thalassemia) (47) and in hexosaminidase A (Tay-Sachs disease) (48) have been identified within this population. At least two alleles cause hyperchylomicronemia in French Canadians (49). In Finland, another region with genetic isolation, population stratification, and characteristic autosomal recessive diseases, at 1190 least three mutant alleles of ornithine 6-amino-transferase cause gyrate atrophy of the choroid and retina, indicating a more complex situation than initially expected (50).…”

Section: Discussionmentioning

confidence: 99%

Type 1 hereditary tyrosinemia. Evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient.

Phaneuf

Lambert²,

Laframboise³

et al. 1992

J. Clin. Invest.

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IntroductionType 1 hereditary tyrosinemia (HT1) is a metabolic disorder caused by a deficiency of fumarylacetoacetate hydrolase (FAH). Using a full-length FAH cDNA and specific antibodies, we investigated liver specimens from seven unrelated HT1 patients (six of French Canadian and one of Scandinavian origin). The expression of FAH in livers of these individuals was analyzed at several molecular levels including mRNA, immunoreactive material (IRM), and enzymatic activity. Four phenotypic variants were differentiated by these assays: (i) presence of FAH mRNA without any IRM or enzymatic activity, (ii) decreased FAH mRNA, IRM, and enzymatic activity, (iii) moderately decreased FAH mRNA and IRM with severely reduced enzymatic activity, and (iv) undetectable FAH mRNA, IRM, and enzymatic activity. These various molecular phenotypes suggest that this disorder may be caused by a variety of FAH mutations. Interestingly, we found no apparent relationship between the clinical and the molecular phenotypes, except that patients with absent IRM and enzymatic activity tend to have higher levels of serum alpha-fetoprotein and an earlier clinical onset. To further analyze the molecular basis of HT1, the FAH cDNA of a patient designated as variant A was amplified and sequenced. An A-to-T transversion, which substitutes asparagine'6 with isoleucine (N161), was identified. This patient was heterozygous as shown by direct sequencing of the amplified region and hybridization with allele-specific oligonucleotide probes. The N161 allele originates from the father and the second allele appears not to be expressed in the liver of the proband. CV-1 cells transfected with the mutant cDNA produced FAH mRNA, but no protein or hydrolytic activity, as predicted by the "A" phenotype of the patient. This is the first demonstration of heterogeneity in the expression of FAH at the levels of protein, mRNA, and enzymatic activity in the livers of HT1 patients and is the first identification of a causal mutationin this disease.

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A Mutation in the Human Lipoprotein Lipase Gene as the Most Common Cause of Familial Chylomicronemia in French Canadians

Cited by 96 publications

References 21 publications

Effect of obesity on HDL and LDL particle sizes in carriers of the null P207L or defective D9N mutation in the lipoprotein lipase gene: the Québec LipD Study

Effect of obesity on HDL and LDL particle sizes in carriers of the null P207L or defective D9N mutation in the lipoprotein lipase gene: the Québec LipD Study

Intestinal fatty acid binding protein and microsomal triglyceride transfer protein polymorphisms in French-Canadian youth

Type 1 hereditary tyrosinemia. Evidence for molecular heterogeneity and identification of a causal mutation in a French Canadian patient.

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