Human Molecular Genetics, 2003, Vol. 12, No. 10 1131-1143
DOI: 10.1093/hmg/ddg124
© 2003 Oxford University Press
Identification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans
1Department of Experimental Therapeutics, Toronto General Research Institute, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada, 2Robarts Research Institute, London, Ontario, Canada, 3The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada, 4University of Victoria, Victoria, British Columbia, Canada, 5Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada, 6Departments of Laboratory Medicine and Pathobiology, University of Toronto and St Michael's Hospital, Toronto, Ontario, Canada and 7McLaughlin Center for Molecular Medicine, Toronto, Ontario, Canada
Received January 3, 2003; Revised February 28, 2003; Accepted March 12, 2003
Triglyceride (TG) metabolism is crucial for whole body and local energy homeostasis and accumulating evidence suggests an independent association between plasma TG concentration and increased atherosclerosis risk. We previously generated a mouse insertional mutation lpd (lipid defect) whose phenotype included elevated plasma TG and hepatic steatosis. Using shotgun sequencing (
500 kb) and bioinformatics, we have now identified a novel lipase gene lpdl (lpd lipase) within the lpd locus, and demonstrate the genetic disruption of exon 10 of lpdl in the lpd mutant locus. lpdl is highly expressed in the testis and weakly expressed in the liver of 2-week old mice. Human LPDL cDNA was subsequently cloned, and was found to encode a 460AA protein with 71% protein sequence identity to mouse lpdl and 35% identity to other known lipases. We next sequenced the human LPDL gene exons in hypertriglyceridemic subjects and normal controls, and identified seven SNPs within the gene exons and six SNPs in the adjacent introns. Two hypertriglyceridemic subjects were heterozygous for a rare DNA variant, namely 164G>A (C55Y), which was absent from 600 normal chromosomes. Two other coding SNPs were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. Using bioinformatics, we identified another novel lipase designated LPDLR (for ‘LPDL related lipase’), which had 44% protein sequence identity with LPDL. Together with the phospholipase gene PSPLA1, LPDL and LPDLR form a new lipase gene subfamily, which is characterized by shortened lid motif. Study of this lipase subfamily may identify novel molecular mechanisms for plasma and/or tissue TG metabolism.
* To whom correspondence should be addressed at: Department of Experimental Therapeutics, Toronto General Research Institute, Toronto General Hospital, Room 410, 67 College Street, Toronto, Ontario, Canada M2M 1E1. Tel: +1 4163403713; Fax: +1 4163403453; Email: x.wen{at}utoronto.ca
Present address: The University of Hong Kong, Pokfulam Road, Hong Kong.
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