A Major Insertion Accounts for a Significant Proportion of Mutations Underlying Human Lipoprotein Lipase Deficiency

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1989 Feb 1

PMID 2536938

Citations 21

Authors

S Langlois

S Deeb

J D Brunzell

J J Kastelein

M R Hayden

Affiliations

Soon will be listed here.

Abstract

Lipoprotein lipase (LPL; triacylglyceroprotein acylhydrolase, EC 3.1.1.34) is an important enzyme involved in triacylglycerol metabolism. Primary LPL deficiency is a genetic disorder that is usually manifested by a severe elevation in triacylglycerol levels. We have used a recently isolated LPL cDNA clone to study 15 probands from 11 families with this inherited disorder. Surprisingly, 7 of the probands from 4 families, of different ancestries, had a similar insertion in their LPL gene. In contrast to other human genetic disorders, where insertions are rare causes of mutation, this insertion accounts for a significant proportion of the alleles causing LPL deficiency. Detailed restriction mapping of the insertion revealed that it was unlikely to be a duplication of neighboring DNA and that it was not similar to the consensus sequence of human L1 repetitive elements. This suggests that there must be other mechanisms of insertional mutagenesis in human genetic disease besides transposition of mobile L1 repetitive elements.

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References

Hayden M, Kirk H, Clark C, Frohlich J, RABKIN S, McLeod R . DNA polymorphisms in and around the Apo-A1-CIII genes and genetic hyperlipidemias. Am J Hum Genet. 1987; 40(5):421-30. PMC: 1684145. View

Iverius P, Brunzell J . Human adipose tissue lipoprotein lipase: changes with feeding and relation to postheparin plasma enzyme. Am J Physiol. 1985; 249(1 Pt 1):E107-14. DOI: 10.1152/ajpendo.1985.249.1.E107. View

Senda M, Oka K, Brown W, Qasba P, Furuichi Y . Molecular cloning and sequence of a cDNA coding for bovine lipoprotein lipase. Proc Natl Acad Sci U S A. 1987; 84(13):4369-73. PMC: 305090. DOI: 10.1073/pnas.84.13.4369. View

Antonarakis S, Youssoufian H, Kazazian Jr H . Molecular genetics of hemophilia A in man (factor VIII deficiency). Mol Biol Med. 1987; 4(2):81-94. View

Forrest S, Cross G, Speer A, Gardner-Medwin D, Burn J, Davies K . Preferential deletion of exons in Duchenne and Becker muscular dystrophies. Nature. 1987; 329(6140):638-40. DOI: 10.1038/329638a0. View

den Dunnen J, Bakker E, Breteler E, Pearson P, van Ommen G . Direct detection of more than 50% of the Duchenne muscular dystrophy mutations by field inversion gels. Nature. 1987; 329(6140):640-2. DOI: 10.1038/329640a0. View

Fisher K, FitzGerald G, Lawn R . Two polymorphisms in the human lipoprotein lipase (LPL) gene. Nucleic Acids Res. 1987; 15(18):7657. PMC: 306290. DOI: 10.1093/nar/15.18.7657. View

Funke H, Klug J, Assmann G . Hind III RFLP in the lipoprotein lipase gene, (LPL). Nucleic Acids Res. 1987; 15(21):9102. PMC: 306448. DOI: 10.1093/nar/15.21.9102. View

Scott A, Schmeckpeper B, Abdelrazik M, Comey C, OHara B, Rossiter J . Origin of the human L1 elements: proposed progenitor genes deduced from a consensus DNA sequence. Genomics. 1987; 1(2):113-25. PMC: 7135745. DOI: 10.1016/0888-7543(87)90003-6. View

10.

Cooley L, Kelley R, Spradling A . Insertional mutagenesis of the Drosophila genome with single P elements. Science. 1988; 239(4844):1121-8. DOI: 10.1126/science.2830671. View

11.

Kazazian Jr H, Wong C, Youssoufian H, Scott A, Phillips D, Antonarakis S . Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature. 1988; 332(6160):164-6. DOI: 10.1038/332164a0. View

12.

Langlois S, Kastelein J, Hayden M . Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH). Am J Hum Genet. 1988; 43(1):60-8. PMC: 1715276. View

13.

Auwerx J, Deeb S, Brunzell J, Peng R, Chait A . Transcriptional activation of the lipoprotein lipase and apolipoprotein E genes accompanies differentiation in some human macrophage-like cell lines. Biochemistry. 1988; 27(8):2651-5. DOI: 10.1021/bi00408a003. View

14.

HAVEL R, GORDON Jr R . Idiopathic hyperlipemia: metabolic studies in an affected family. J Clin Invest. 1960; 39:1777-90. PMC: 441903. DOI: 10.1172/JCI104202. View

15.

HARLAN Jr W, Winesett P, WASSERMAN A . 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; 46(2):239-47. PMC: 297042. DOI: 10.1172/JCI105526. View

16.

Krauss R, Levy R, Fredrickson D . Selective measurement of two lipase activities in postheparin plasma from normal subjects and patients with hyperlipoproteinemia. J Clin Invest. 1974; 54(5):1107-24. PMC: 301659. DOI: 10.1172/JCI107855. View

17.

Southern E . Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975; 98(3):503-17. DOI: 10.1016/s0022-2836(75)80083-0. View

18.

Stout J, Caskey C . HPRT: gene structure, expression, and mutation. Annu Rev Genet. 1985; 19:127-48. DOI: 10.1146/annurev.ge.19.120185.001015. View

19.

Lehrman M, Russell D, Goldstein J, Brown M . Alu-Alu recombination deletes splice acceptor sites and produces secreted low density lipoprotein receptor in a subject with familial hypercholesterolemia. J Biol Chem. 1987; 262(7):3354-61. View

20.

Wion K, Kirchgessner T, Lusis A, Schotz M, Lawn R . Human lipoprotein lipase complementary DNA sequence. Science. 1987; 235(4796):1638-41. DOI: 10.1126/science.3823907. View