Heterozygous familial hypercholesterolemia in children: low-density lipoprotein receptor mutational analysis and variation in the expression of plasma lipoprotein-lipid concentrations

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      The phenotypic expression of heterozygous familial hypercholesterolemia (FH) is variable from biochemical and clinical standpoints and several genetic and environmental factors could contribute to explain this variability. We have compared, in a cohort of 266 heterozygous FH children and adolescents (1–19 years), the variation in plasma lipoprotein-lipid levels among patients defined by three mutations in the low density lipoprotein receptor (LDLR) gene. Comparison of the plasma total and LDL-cholesterol (LDL-C) levels among the three mutation groups revealed significant differences. Plasma total and LDL-C levels were significantly higher (P < 0.05) in the group bearing the French-Canadian Δ > 15 kb null allele mutation (8.17 ± 1.45 and 6.58 ± 1.42 mmol/l) and in the group with the defective allele C646Y missense mutation (8.18 ± 1.53 and 6.65 ± 1.50 mmol/l) compared to the group with the defective allele W66G missense mutation (7.19 ± 1.23 and 5.62 ± 1.16 mmol/l). Comparisons of other lipoprotein-lipid parameters between FH heterozygotes and normolipemic (n = 120) children indicated that all mutation groups had significantly (P = 0.0001) lower plasma HDL-cholesterol (HDL-C) levels and a higher total cholesterol (TC) to HDL-C ratio (P < 0.05). Among FH heterozygote groups, the W66G group had the lowest TC to HDL-C ratio. Multivariate analyses revealed that in FH heterozygotes as well as in controls, HDL-C levels contributed to a greater proportion of the variation in TC to HDL-C ratio than TC. In order to examine the age effect, control and FH heterozygote Δ > 15 kb groups were then subdivided into four groups (1–4; 5–8; 9–13, and 14–19 years). The variation in HDL-C and triglycerides with age in heterozygous FH children showed a pattern which was similar to the one noted in the control group. In conclusion, the present study demonstrated that the overall contribution of age to variation in the lipoprotein profile of heterozygous FH children is similar to the effect observed among healthy children. The effect of LDLR gene in FH is dominant and there was no difference in plasma TC and LDL-C due to gender. Finally, this study indicates that the LDLR gene type mutations are a modulator of the magnitude of the increase in plasma TC and LDL-C levels noted among FH heterozygote children.


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        • Brown MS
        • Goldstein JL
        A receptor mediated pathway for cholesterol homeostasis.
        Science. 1986; 232: 34-47
        • Kwiterovich Jr, PO
        Biochemical, clinical, epidemiologic, genetic, and pathologic data in the pediatric age group relevant to the cholesterol hypothesis.
        Pediatrics. 1986; 78: 349-362
        • Stary Hebert C
        Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults.
        Arteriosclerosis. 1989; 9: I-19-I-32
        • Strong JP
        • McGill Jr, HC
        The pediatric aspects of atherosclerosis.
        J Atheroscler Res. 1969; 9: 251-265
        • Kwiterovich Jr, PO
        • Fredrickson SD
        • Levy RI
        Familial hypercholesterolemia (one form of familial type II hyperlipoproteinemia). A study of its biochemical, genetic, and clinical presentation in childhood.
        J Clin Invest. 1974; 53: 1237-1249
        • Goldstein JL
        • Hobbs HH
        • Brown MS
        Familial hypercholesterolemia.
        in: Scriver CR Beaudet AL Sly WS Valle D The Metabolic and Molecular Bases of Inherited Diseases. 7th edn. McGraw-Hill, New York1995: 1981-2030
        • Hobbs HH
        • Russell DW
        • Brown MS
        • Goldstein JL
        The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.
        Annu Rev Genet. 1990; 24: 133-170
        • Leitersdorf E
        • van der Westhuyzen DR
        • Coetzee GA
        • Hobbs HH
        Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners.
        J Clin Invest. 1989; 84: 954-961
        • Lehrman MA
        • Schneider WJ
        • Brown MS
        • et al.
        The lebanese allele at the low density lipoprotein receptor locus: non-sense mutation produces truncated receptor that is retained in endoplasmic reticulum.
        J Biol Chem. 1987; 262: 401-410
        • Seftel HC
        • Baker SG
        • Jenkins T
        • Mendelson D
        Prevalence of familial hypercholesterolemia in Johannesburg jews.
        Am J Med Genet. 1989; 34: 545-547
        • Aalto-Setälä K
        • Helve KE
        • Konaven T
        • Kontula K
        Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.
        J Clin Invest. 1989; 84: 499-505
        • Slimane MN
        • Pousse H
        • Maatoug F
        • Hammami M
        • Ben Farhat MH
        Phenotypic expression of familial hypercholesterolaemia in Central and Southern Tunisia.
        Atherosclerosis. 1993; 104: 153-158
        • Hobbs HH
        • Brown MS
        • Russell DW
        • Davignon J
        • Goldstein JL
        Deletion in the gene for the low density lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia.
        New Engl J Med. 1987; 317: 734-737
        • Leitersdorf E
        • Tobin EJ
        • Davignon J
        • Hobbs HH
        Common low-density lipoprotein receptor mutations in the French Canadian population.
        J Clin Invest. 1990; 85: 1014-1023
        • Ma Y
        • Bétard C
        • Roy M
        • Davignon J
        • Kessling AM
        Identification of a second ⪡French Canadian⪢ LDL receptor gene deletion and development of a rapid method to detect both deletions.
        Clin Genet. 1989; 36: 219-228
        • Simard J
        • Moorjani S
        • Vohl M-C
        • et al.
        Detection of a novel mutation (stop 468) in exon 10 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.
        Hum Mol Genet. 1994; 3: 1689-1691
        • Gagné C
        • Moorjani S
        • Brun D
        • Toussaint M
        • Lupien P-J
        Heterozygous familial hypercholesterolemia. Relationship between plasma lipids, lipoprotein, clinical manifestations and ischaemic heart disease in men and women.
        Atherosclerosis. 1979; 34: 13-24
        • Burstein M
        • Samaille J
        Sur un dosage rapide du cholestérol lié aux alpha et aux bêta-lipoprotéines du sérum.
        Clin Chim Acta. 1960; 5: 609-610
        • Friedewald WT
        • Levy RI
        • Fredrickson DS
        Estimation of the concentration of low-density lipoprotein in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Sambrook J
        • Fritsh EF
        • Maniatis T
        2nd edn. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press, New York1989
        • Feinberg AP
        • Vogelstein B
        A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity.
        Anal Biochem. 1983; 132: 6-13
        • Vohl M-C
        • Couture P
        • Moorjani S
        • et al.
        Rapid restriction fragment analysis for screening four point mutations of the low-density lipoprotein receptor gene in French Canadians.
        Hum Mut. 1995; 6: 243-246
        • Castelli WP
        • Abbott RD
        • McNamara PM
        Summary estimates of cholesterol used to predict coronary heart disease.
        Circulation. 1983; 67: 730-734
        • Russell DW
        • Brown MS
        • Goldstein JL
        Different combinations of cysteine-rich repeats mediate binding of low density lipoprotein receptor to two different proteins.
        J Biol Chem. 1989; 264: 21682-21688
        • Hobbs HH
        • Brown MS
        • Goldstein JL
        Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.
        Hum Mut. 1992; 1: 445-466
        • Srinivasan SR
        • Frerichs RR
        • Webber LS
        • Berenson GS
        Serum lipoprotein profile in children from a biracial community. The Bogalusa Heart Study.
        Circulation. 1976; 54: 309-318
        • Rifkind BM
        • Segal P
        Lipid Research Clinics program reference values for hyperlipidemia and hypolipidemia.
        J Am Med Assoc. 1983; 250: 1869-1872
        • Assmann G
        • Schulte H
        Relation to high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease. (The PROCAM Experience).
        Am J Cardiol. 1992; 70: 733-737
        • Castelli William P
        Epidemiology of triglycerides: a view from Framingham.
        Am J Cardiol. 1992; 70: 3H-9H
        • Reaven GM
        • Ida Chen YD
        • Jeppesen J
        • Maheux P
        • Krauss RM
        Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles.
        J Clin Invest. 1993; 92: 141-146
        • Lamarche B
        • Després JP
        • Pouliot MC
        • et al.
        Metabolic heterogeneity associated with high plasma triglyceride or low HDL cholesterol levels in men.
        Arterioscler Thromb. 1993; 13: 33-40
        • Moorjani S
        • Gagné C
        • Lupien P-J
        • Brun D
        Plasma triglycerides related decrease in high-density lipoprotein cholesterol and its association with myocardial infarction in heterozygous familial hypercholesterolemia.
        Metabolism. 1986; 35: 311-316
        • Freedman DS
        • Srinivasan SR
        • Voors AW
        • Webber LS
        • Berenson GS
        High density lipoprotein and coronary artery disease risk factors in children with different lipoprotein profiles: Bogalusa Heart Study.
        J Chronic Dis. 1985; 38: 327-338