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. 1990 Sep;86(3):735–750. doi: 10.1172/JCI114770

Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation.

D E Wilson 1, M Emi 1, P H Iverius 1, A Hata 1, L L Wu 1, E Hillas 1, R R Williams 1, J M Lalouel 1
PMCID: PMC296788  PMID: 2394828

Abstract

Familial lipoprotein lipase (LPL) deficiency is a rare genetic disorder accompanied by well-characterized manifestations. The phenotypic expression of heterozygous LPL deficiency has not been so clearly defined. We studied the pedigree of a proband known to be homozygous for a mutation resulting in nonfunctional LPL. Hybridization of DNA from 126 members with allele-specific probes detected 29 carriers of the mutant allele. Adipose tissue LPL activity, measured previously, was reduced by 50% in carriers, but did not reliably distinguish them from noncarriers. Carriers were prone to the expression of a form of familial hypertriglyceridemia characterized by increased plasma triglyceride, VLDL cholesterol and apolipoprotein B, and decreased LDL and HDL cholesterol concentrations. These manifestations were age modulated, with conspicuous differences between carriers and noncarriers observed only after age 40. Several noncarriers exhibited similar lipid abnormalities, but without the inverse relationship between VLDL cholesterol and LDL cholesterol noted among carriers. In addition to age and carrier status, the potentially reversible conditions, obesity, hyperinsulinemia and lipid-raising drug use were contributory. Thus heterozygous lipoprotein lipase deficiency, together with age-related influences, may account for a form of familial hypertriglyceridemia.

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Selected References

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  1. Auwerx J. H., Babirak S. P., Fujimoto W. Y., Iverius P. H., Brunzell J. D. Defective enzyme protein in lipoprotein lipase deficiency. Eur J Clin Invest. 1989 Oct;19(5):433–437. doi: 10.1111/j.1365-2362.1989.tb00255.x. [DOI] [PubMed] [Google Scholar]
  2. Babirak S. P., Iverius P. H., Fujimoto W. Y., Brunzell J. D. Detection and characterization of the heterozygote state for lipoprotein lipase deficiency. Arteriosclerosis. 1989 May-Jun;9(3):326–334. doi: 10.1161/01.atv.9.3.326. [DOI] [PubMed] [Google Scholar]
  3. Beil U., Grundy S. M., Crouse J. R., Zech L. Triglyceride and cholesterol metabolism in primary hypertriglyceridemia. Arteriosclerosis. 1982 Jan-Feb;2(1):44–57. doi: 10.1161/01.atv.2.1.44. [DOI] [PubMed] [Google Scholar]
  4. Berger G. M., Bonnici F. Familial hyperchylomicronaemia in four families. Problems in diagnosis, management, and aetiology reviewed. S Afr Med J. 1977 Apr 30;51(18):623–628. [PubMed] [Google Scholar]
  5. Berson S. A., Yalow R. S. Some current controversies in diabetes research. Diabetes. 1965 Sep;14(9):549–572. doi: 10.2337/diab.14.9.549. [DOI] [PubMed] [Google Scholar]
  6. Bevilacqua S., Bonadonna R., Buzzigoli G., Boni C., Ciociaro D., Maccari F., Giorico M. A., Ferrannini E. Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism. 1987 May;36(5):502–506. doi: 10.1016/0026-0495(87)90051-5. [DOI] [PubMed] [Google Scholar]
  7. Breckenridge W. C., Little J. A., Steiner G., Chow A., Poapst M. Hypertriglyceridemia associated with deficiency of apolipoprotein C-II. N Engl J Med. 1978 Jun 8;298(23):1265–1273. doi: 10.1056/NEJM197806082982301. [DOI] [PubMed] [Google Scholar]
  8. Brunzell J. D., Hazzard W. R., Porte D., Jr, Bierman E. L. Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. J Clin Invest. 1973 Jul;52(7):1578–1585. doi: 10.1172/JCI107334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brunzell J. D., Iverius P. H., Scheibel M. S., Fujimoto W. Y., Hayden M. R., McLeod R., Frolich J. Primary lipoprotein lipase deficiency. Adv Exp Med Biol. 1986;201:227–239. doi: 10.1007/978-1-4684-1262-8_20. [DOI] [PubMed] [Google Scholar]
  10. Chait A., Albers J. J., Brunzell J. D. Very low density lipoprotein overproduction in genetic forms of hypertriglyceridaemia. Eur J Clin Invest. 1980 Feb;10(1):17–22. doi: 10.1111/j.1365-2362.1980.tb00004.x. [DOI] [PubMed] [Google Scholar]
  11. Deeb S. S., Peng R. L. Structure of the human lipoprotein lipase gene. Biochemistry. 1989 May 16;28(10):4131–4135. doi: 10.1021/bi00436a001. [DOI] [PubMed] [Google Scholar]
  12. Dunn F. L., Grundy S. M., Bilheimer D. W., Havel R. J., Raskin P. Impaired catabolism of very low-density lipoprotein-triglyceride in a family with primary hypertriglyceridemia. Metabolism. 1985 Apr;34(4):316–324. doi: 10.1016/0026-0495(85)90220-3. [DOI] [PubMed] [Google Scholar]
  13. Eaton B. P., Nye W. H. The relationship between insulin secretion and triglyceride concentration in endogenous lipemia. J Lab Clin Med. 1973 May;81(5):682–695. [PubMed] [Google Scholar]
  14. Emi M., Wilson D. E., Iverius P. H., Wu L., Hata A., Hegele R., Williams R. R., Lalouel J. M. Missense mutation (Gly----Glu188) of human lipoprotein lipase imparting functional deficiency. J Biol Chem. 1990 Apr 5;265(10):5910–5916. [PubMed] [Google Scholar]
  15. Fellin R., Baggio G., Poli A., Augustin J., Baiocchi M. R., Baldo G., Sinigaglia M., Greten H., Crepaldi G. Familial lipoprotein lipase and apolipoprotein C-II deficiency. Lipoprotein and apoprotein analysis, adipose tissue and hepatic lipoprotein lipase levels in seven patients and their first degree relatives. Atherosclerosis. 1983 Oct;49(1):55–68. doi: 10.1016/0021-9150(83)90007-2. [DOI] [PubMed] [Google Scholar]
  16. Ferrannini E., Barrett E. J., Bevilacqua S., DeFronzo R. A. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983 Nov;72(5):1737–1747. doi: 10.1172/JCI111133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fredrickson D. S., Levy R. I., Lees R. S. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967 Jan 19;276(3):148–contd. doi: 10.1056/NEJM196701192760305. [DOI] [PubMed] [Google Scholar]
  18. Gagne C., Brun D., Moorjani S., Lupien P. J. Hyperchylomicronémie familiale: étude de l'activité lipolytique dans une famille. Union Med Can. 1977 Mar;106(3):333–338. [PubMed] [Google Scholar]
  19. Glueck C. J., Levy R. I., Fredrickson D. S. Immunoreactive insulin, glucose tolerance, and carbohydrate inducibility in types II, 3, IV, and V hyperlipoproteinemia. Diabetes. 1969 Nov;18(11):739–747. doi: 10.2337/diab.18.11.739. [DOI] [PubMed] [Google Scholar]
  20. Goldberg A. P., Chait A., Brunzell J. D. Postprandial adipose tissue lipoprotein lipase activity in primary hypertriglyceridemia. Metabolism. 1980 Mar;29(3):223–229. doi: 10.1016/0026-0495(80)90063-3. [DOI] [PubMed] [Google Scholar]
  21. Goldstein J. L., Hazzard W. R., Schrott H. G., Bierman E. L., Motulsky A. G. Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest. 1973 Jul;52(7):1533–1543. doi: 10.1172/JCI107331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Goldstein J. L., Schrott H. G., Hazzard W. R., Bierman E. L., Motulsky A. G. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973 Jul;52(7):1544–1568. doi: 10.1172/JCI107332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Greenberg B. H., Blackwelder W. C., Levy R. I. Primary type V hyperlipoproteinemia. A descriptive study in 32 families. Ann Intern Med. 1977 Nov;87(5):526–534. doi: 10.7326/0003-4819-87-5-526. [DOI] [PubMed] [Google Scholar]
  24. Greenfield M. S., Kraemer F., Tobey T., Reaven G. Effect of age on plasma triglyceride concentrations in man. Metabolism. 1980 Oct;29(11):1095–1099. doi: 10.1016/0026-0495(80)90221-8. [DOI] [PubMed] [Google Scholar]
  25. Grundy S. M., Mok H. Y., Zech L., Steinberg D., Berman M. Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia. J Clin Invest. 1979 Jun;63(6):1274–1283. doi: 10.1172/JCI109422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Grundy S. M. Pathogenesis of hyperlipoproteinemia. J Lipid Res. 1984 Dec 15;25(13):1611–1618. [PubMed] [Google Scholar]
  27. Grundy S. M., Vega G. L. Hypertriglyceridemia: causes and relation to coronary heart disease. Semin Thromb Hemost. 1988 Apr;14(2):149–164. doi: 10.1055/s-2007-1002769. [DOI] [PubMed] [Google Scholar]
  28. Harlan W. R., Jr, Winesett P. S., Wasserman A. J. Tissue lipoprotein lipase in normal individuals and in individuals with exogenous hypertriglyceridemia and the relationship of this enzyme to assimilation of fat. J Clin Invest. 1967 Feb;46(2):239–247. doi: 10.1172/JCI105526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Huttunen J. K., Ehnholm C., Kekki M., Nikkilä E. A. Post-heparin plasma lipoprotein lipase and hepatic lipase in normal subjects and in patients with hypertriglyceridaemia: correlations to sex, age and various parameters of triglyceride metabolism. Clin Sci Mol Med. 1976 Apr;50(4):249–260. doi: 10.1042/cs0500249. [DOI] [PubMed] [Google Scholar]
  30. Huttunen J. K., Ehnholm C., Nikkilä E. A., Ohta M. Effect of fasting on two postheparin plasma triglyceride lipases and triglyceride removal in obese subjects. Eur J Clin Invest. 1975 Nov 21;5(6):435–445. doi: 10.1111/j.1365-2362.1975.tb00475.x. [DOI] [PubMed] [Google Scholar]
  31. Janus E. D., Nicoll A. M., Turner P. R., Magill P., Lewis B. Kinetic bases of the primary hyperlipidaemias: studies of apolipoprotein B turnover in genetically defined subjects. Eur J Clin Invest. 1980 Apr;10(2 Pt 1):161–172. doi: 10.1111/j.1365-2362.1980.tb02076.x. [DOI] [PubMed] [Google Scholar]
  32. KESSLER J. I. Effect of diabetes and insulin on the activity of myocardial and adipose tissue lipoprotein lipase of rats. J Clin Invest. 1963 Mar;42:362–367. doi: 10.1172/JCI104722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kekki M. Lipoprotein-lipase action determining plasma high density lipoprotein cholesterol level in adult normolipaemics. Atherosclerosis. 1980 Sep;37(1):143–150. doi: 10.1016/0021-9150(80)90102-1. [DOI] [PubMed] [Google Scholar]
  34. Kesaniemi Y. A., Grundy S. M. Dual defect in metabolism of very-low-density lipoprotein triglycerides. Patients with type 5 hyperlipoproteinemia. JAMA. 1984 May 18;251(19):2542–2547. [PubMed] [Google Scholar]
  35. Kissebah A. H., Alfarsi S., Adams P. W. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia. Metabolism. 1981 Sep;30(9):856–868. doi: 10.1016/0026-0495(81)90064-0. [DOI] [PubMed] [Google Scholar]
  36. Krauss R. M., Levy R. I., Fredrickson D. S. Selective measurement of two lipase activities in postheparin plasma from normal subjects and patients with hyperlipoproteinemia. J Clin Invest. 1974 Nov;54(5):1107–1124. doi: 10.1172/JCI107855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kuusi T., Ehnholm C., Viikari J., Härkönen R., Vartiainen E., Puska P., Taskinen M. R. Postheparin plasma lipoprotein and hepatic lipase are determinants of hypo- and hyperalphalipoproteinemia. J Lipid Res. 1989 Aug;30(8):1117–1126. [PubMed] [Google Scholar]
  38. Langlois S., Deeb S., Brunzell J. D., Kastelein J. J., Hayden M. R. A major insertion accounts for a significant proportion of mutations underlying human lipoprotein lipase deficiency. Proc Natl Acad Sci U S A. 1989 Feb;86(3):948–952. doi: 10.1073/pnas.86.3.948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lees R. S., Fredrickson D. S. The differentiation of exogenous and endogenous hyperlipemia by paper electrophoresis. J Clin Invest. 1965 Dec;44(12):1968–1977. doi: 10.1172/JCI105303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Lees R. S., Wilson D. E., Schonfeld G., Fleet S. The familial dyslipoproteinemias. Prog Med Genet. 1973;9:237–290. [PubMed] [Google Scholar]
  41. Meylan M., Henny C., Temler E., Jéquier E., Felber J. P. Metabolic factors in the insulin resistance in human obesity. Metabolism. 1987 Mar;36(3):256–261. doi: 10.1016/0026-0495(87)90185-5. [DOI] [PubMed] [Google Scholar]
  42. Minnich A., Nordestgaard B. G., Zilversmit D. B. A novel explanation for the reduced LDL cholesterol in severe hypertriglyceridemia. J Lipid Res. 1989 Mar;30(3):347–355. [PubMed] [Google Scholar]
  43. Modan M., Halkin H., Lusky A., Segal P., Fuchs Z., Chetrit A. Hyperinsulinemia is characterized by jointly disturbed plasma VLDL, LDL, and HDL levels. A population-based study. Arteriosclerosis. 1988 May-Jun;8(3):227–236. doi: 10.1161/01.atv.8.3.227. [DOI] [PubMed] [Google Scholar]
  44. Nikkilä E. A., Huttunen J. K., Ehnholm C. Postheparin plasma lipoprotein lipase and hepatic lipase in diabetes mellitus. Relationship to plasma triglyceride metabolism. Diabetes. 1977 Jan;26(1):11–21. doi: 10.2337/diab.26.1.11. [DOI] [PubMed] [Google Scholar]
  45. Nikkilä E. A., Kekki M. Plasma triglyceride transport kinetics in diabetes mellitus. Metabolism. 1973 Jan;22(1):1–22. doi: 10.1016/0026-0495(73)90024-3. [DOI] [PubMed] [Google Scholar]
  46. Nikkilä E. A., Taskinen M. R., Sane T. Plasma high-density lipoprotein concentration and subfraction distribution in relation to triglyceride metabolism. Am Heart J. 1987 Feb;113(2 Pt 2):543–548. doi: 10.1016/0002-8703(87)90629-6. [DOI] [PubMed] [Google Scholar]
  47. Olefsky J. M., Farquhar J. W., Reaven G. M. Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med. 1974 Oct;57(4):551–560. doi: 10.1016/0002-9343(74)90006-0. [DOI] [PubMed] [Google Scholar]
  48. Ong J. M., Kirchgessner T. G., Schotz M. C., Kern P. A. Insulin increases the synthetic rate and messenger RNA level of lipoprotein lipase in isolated rat adipocytes. J Biol Chem. 1988 Sep 15;263(26):12933–12938. [PubMed] [Google Scholar]
  49. Packard C. J., Shepherd J., Joerns S., Gotto A. M., Taunton O. D. Apolipoprotein B metabolism in normal, type IV and type V hyperlipoproteinemic subjects. Metabolism. 1980 Mar;29(3):213–222. doi: 10.1016/0026-0495(80)90062-1. [DOI] [PubMed] [Google Scholar]
  50. Persson B. Lipoprotein lipase activity of huuman adipose tissue in different types of hyperlipidemia. Acta Med Scand. 1973 May;193(5):447–456. doi: 10.1111/j.0954-6820.1973.tb10607.x. [DOI] [PubMed] [Google Scholar]
  51. Reaven G. M., Hill D. B., Gross R. C., Farquhar J. W. Kinetics of triglyceride turnover of very low density lipoproteins of human plasma. J Clin Invest. 1965 Nov;44(11):1826–1833. doi: 10.1172/JCI105290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Reaven G. M., Lerner R. L., Stern M. P., Farquhar J. W. Role of insulin in endogenous hypertriglyceridemia. J Clin Invest. 1967 Nov;46(11):1756–1767. doi: 10.1172/JCI105666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Saku K., Gartside P. S., Hynd B. A., Mendoza S. G., Kashyap M. L. Apolipoprotein AI and AII metabolism in patients with primary high-density lipoprotein deficiency associated with familial hypertriglyceridemia. Metabolism. 1985 Aug;34(8):754–764. doi: 10.1016/0026-0495(85)90027-7. [DOI] [PubMed] [Google Scholar]
  54. Sane T., Nikkilä E. A. Very low density lipoprotein triglyceride metabolism in relatives of hypertriglyceridemic probands. Evidence for genetic control of triglyceride removal. Arteriosclerosis. 1988 May-Jun;8(3):217–226. doi: 10.1161/01.atv.8.3.217. [DOI] [PubMed] [Google Scholar]
  55. Stalenhoef A. F., Demacker P. N., Lutterman J. A., van 't Laar A. Plasma lipoproteins, apolipoproteins, and triglyceride metabolism in familial hypertriglyceridemia. Arteriosclerosis. 1986 Jul-Aug;6(4):387–394. doi: 10.1161/01.atv.6.4.387. [DOI] [PubMed] [Google Scholar]
  56. Taskinen M. R., Nikkilä E. A., Kuusi T. Lipoprotein lipase activity of adipose tissue, skeletal muscle and post-heparin plasma in primary endogenous hypertriglyceridaemia: relation to lipoprotein pattern and to obesity. Eur J Clin Invest. 1982 Oct;12(5):433–438. doi: 10.1111/j.1365-2362.1982.tb00692.x. [DOI] [PubMed] [Google Scholar]
  57. Taylor K. G., Holdsworth G., Galton D. J. Lipoprotein lipase and adipose tissue and plasma triglyceride clearance in patients with primary hypertriglyceridaemia. Eur J Clin Invest. 1980 Apr;10(2 Pt 1):133–138. doi: 10.1111/j.1365-2362.1980.tb02072.x. [DOI] [PubMed] [Google Scholar]
  58. Thiébaud D., DeFronzo R. A., Jacot E., Golay A., Acheson K., Maeder E., Jéquier E., Felber J. P. Effect of long chain triglyceride infusion on glucose metabolism in man. Metabolism. 1982 Nov;31(11):1128–1136. doi: 10.1016/0026-0495(82)90163-9. [DOI] [PubMed] [Google Scholar]
  59. Warnick G. R., Benderson J., Albers J. J. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem. 1982 Jun;28(6):1379–1388. [PubMed] [Google Scholar]
  60. Wilson D. E., Edwards C. Q., Chan I. F. Phenotypic heterogeneity in the extended pedigree of a proband with lipoprotein lipase deficiency. Metabolism. 1983 Dec;32(12):1107–1114. doi: 10.1016/0026-0495(83)90056-2. [DOI] [PubMed] [Google Scholar]
  61. Wilson D. E., Glad B. W., Working P. K., Adler M. E. Postheparin plasma lipase activities in obesity: failure to increase with adipose organ enlargement. Metabolism. 1978 Sep;27(9):1084–1094. doi: 10.1016/0026-0495(78)90154-3. [DOI] [PubMed] [Google Scholar]
  62. Wilson D. E., Zeikus R., Chan I. F. Relationship of organ lipoprotein lipase activity and ketonuria to hypertriglyceridemia in starved and streptozocin-induced diabetic rats. Diabetes. 1987 Apr;36(4):485–490. doi: 10.2337/diab.36.4.485. [DOI] [PubMed] [Google Scholar]
  63. Wion K. L., Kirchgessner T. G., Lusis A. J., Schotz M. C., Lawn R. M. Human lipoprotein lipase complementary DNA sequence. Science. 1987 Mar 27;235(4796):1638–1641. doi: 10.1126/science.3823907. [DOI] [PubMed] [Google Scholar]
  64. Wu L. L., Warnick G. R., Wu J. T., Williams R. R., Lalouel J. M. A rapid micro-scale procedure for determination of the total lipid profile. Clin Chem. 1989 Jul;35(7):1486–1491. [PubMed] [Google Scholar]
  65. Zech L. A., Grundy S. M., Steinberg D., Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects. J Clin Invest. 1979 Jun;63(6):1262–1273. doi: 10.1172/JCI109421. [DOI] [PMC free article] [PubMed] [Google Scholar]

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