Abstract
The enzyme lipoprotein lipase (LPL) plays a crucial role in triglyceride metabolism through catalysis of triglyceride-rich chylomicrons and very low density lipoproteins. Primary LPL deficiency manifests with chylomicronaemia and is caused by mutations in the LPL gene. In this paper we report a novel molecular defect (G670→A) in exon 4 of the LPL gene, resulting in a substitution of serine for glycine at position 139 in the mature protein. We identified homozygosity for this mutation in a boy of Spanish descent. In vitro mutagenesis provided formal proof that this missense mutation completely abolishes LPL function and therefore is the cause of LPL deficiency.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abeling NGGM, Bakker HD, Van Gennip AH (1981) Biochemical findings in a patient with lipoprotein lipase deficiency (hyperlipoproteinemia type I). J Inherited Metab Dis 4:175–176
Ameis D, Kobayashi J, Davis RC, Ben-Zeev O, Malloy MJ, Kane JP, Lee G, Wong H, Greten H, Havel RJ, Schotz MC (1990) Familial hyperchylomicronemia associated with a missense mutation in the lipoprotein lipase gene. J Clin Invest 87:1165–1170
Babirak SP, Iverius PH, Fujimoto WY, Brunzell JD (1989) Detection and characterisation of the heterozygote state for lipoprotein lipase deficiency. Arteriosclerosis 9:326–334
Bruin T, Reijmer PWE, Groenemeijer BE, Talmud PJ, Kastelein JJP (1991) HindIII polymorphism in the lipoprotein lipase gene, detected by polymerase chain reaction. Nucleic Acids Res 19:6346
Bruin T, Tuzgöl S, Diermen DE Van, Hoogerbrugge van der Linden N, Brunzell gnJD, Hayden MR, Kastelein JJP (1993) Recurrent pancreatitis and chylomicronemia in an extended Dutch kindred is caused by a Gly154→Ser substitution in lipoprotein lipase. J Lipid Res 34 (in press)
Church GM, Gilbert W (1984) Genomic sequencing. Nucleic Acids Res 18:1991–1995
Deeb SS, Peng R (1989) Structure of the human lipoprotein lipase gene. Biochemistry 28:4131–4135
Deeb SS, Reina M, Peterson J, Takata K, Kajiyama G, Brunzell JD (1991) Gene mutations in patients with lipoprotein lipase deficiency (abstract). Arteriosclerosis Thromb 11:1418
Derewenda ZS, Cambillau C (1991) Effects of gene mutations in lipoprotein and hepatic lipase as interpreted by a molecular model of the pancreatic triglyceride lipase. J Biol Chem 266:23119–23112
Derewenda ZS, Derewenda U (1991) Relationships among serine hydrolases: evidence for a common structural motif in triacylglyceride lipases and esterases. Biochem Cell Biol 69:842–851
Eckel RH (1989) Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases. N Engl J Med 320:1060–1068
Enerback S, Bjursell G (1989) Genomic organisation of the region encoding guinea pig lipoprotein lipase; evidence for exon fusion and unconventional splicing. Gene 84:391–397
Faustinella F, Smith LC, Semenkovich CF, Chan L (1991) Structural and functional roles of highly conserved serines in human lipoprotein lipase. J Biol Chem 266:9481–9485
Feinberg AP, Vogelstein B (1984) A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 137:266–267
Fojo SS (1992) Genetic dyslipoproteinemias: role of lipoprotein lipase and apolipoprotein CII. Curr Opin Lipid 3:186–195
Gagné C, Brum LD, Julien P, Moorjani S, Lupien PJ (1989) Primary lipoprotein lipase activity deficiency: clinical investigation of a French-Canadian population. Can Med Assoc J 140:405–411
Hayden MR, Kirk H, Macleod R, Frohlich J, Rabkin S, Hewitt J (1986) DNA polymorphisms in and around the apoAI-CIII genes and genetic hyperlipidemias. Am J Hum Genet 40:421–430
Iverius PH, Brunzell JD (1985) Human adipose tissue lipoprotein lipase: changes with feeding and relationship to post heparin plasma enzyme. Am J Physiol 249:E1–07-E114
Johnson JP, Nishina PM, Naggert JK (1992) Polymerase chain assay for a polymorphic PvuII site in the lipoprotein lipase gene. Nucleic Acids Res 18:7469
Kirchgessner TG, Chuat JC, Heinzmann C, Etienne J, Guilhot S, Svenson K (1989) Organisation of the human lipoprotein lipase gene and evolution of the lipase gene family. Proc Natl Acad Sci USA 86:9647–9651
Ma Y, Bruin T, Tuzgöl S, Wilson BI, Roederer G, Lin MS, Davignon J, Kastelein JJP, Brunzell JD, Hayden MR (1992) Two naturally occurring mutations in the first and second bases of codon aspartic acid 156 in the proposed catalytic triad on human lipoprotein lipase, In vivo evidence that aspartic acid 156 is essential for catalysis. J Biol Chem 267:1918–1923
Monsalve MV, Henderson HE, Roederer G, Julien P, Deeb S, Kastelein JJP, Peritz L, Bruin T, Murthy MRV, Gagné C, Davignon J, Lupien PJ, Brunzell JD, Hayden MR (1990) A missense mutation at codon 188 of the human lipoprotein lipase gene is a frequent cause of lipoprotein lipase deficiency in persons of different ancestries. J Clin Invest 86:728–734
Olivecrona T, Bengtsson-Olivecrona G (1987) Lipoprotein lipase from milk — the model enzyme in lipoprotein lipase research. In: Borenszatajn J (ed) Lipoprotein lipase. Evener, Chicago, pp 15–58
Persson B, Bengtsson-Olivecrona G, Enerback S, Olivecrona T, Jornvall H (1989) Structural features of lipoprotein lipase. Lipase family relationships, binding interactions, non-equivalents of lipase cofactors, vitellogen similarities and functional subdivisions of lipoprotein lipase. Eur J Biochem 179:39–45
Peterson J, Bilhain BE, Bengtsson-Olivecrona G, Deckelbaum RJ, Carpentier YA, Olivecrona T (1990) Fatty acid control of lipoprotein lipase: a link between energy metabolism and lipid transport. Proc Natl Acad Sci USA 87:909–913
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electorphoresis. J Mol Biol 98:503–517
Sparkes RS, Zollman S, Klisak I, Kirchgessner TG, Komaromy C, Mohamdas T (1987) Human genes involved in lipolysis of plasma lipoproteins: mapping of loci for lipoprotein lipase to 8p22 and hepatic lipase to 15q21. Genomics 1:138–144
Warnick GA, Albers JJ (1978) A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high density lipoprotein cholesterol. J Lipid Res 19:65–76
Wilson DE, Spiger MJ (1973) A dual precipitation method for quantitative plasma lipoprotein measurements without ultracentrifugation. J Lab Clin Med 82:473–482
Wion KL, Kirchgessner TG, Lusis AJ, Schotz MC, Lawn RM (1987) Human lipoprotein lipase complementary cDNA sequence. Science 235:1638–1641
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bijvoet, S.M., Bruin, T., Thzgöl, S. et al. Homozygosity for a mutation in the lipoprotein lipase gene (Gly139→Ser) causes chylomicronaemia in a boy of Spanish descent. Hum Genet 93, 339–343 (1994). https://doi.org/10.1007/BF00212035
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00212035