Article: Identification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans

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TitleIdentification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans
AuthorsWen, XY2 5
Hegele, RA4
Wang, J4
Yan Wang, D5
Cheung, J8
Wilson, M6
Yahyapour, M5
Bai, Y5
Zhuang, L5
Skaug, J8
Young, TK7
Connelly, PW3
Koop, BF6
Tsui, LC1 8
Stewart, AK2 5
Issue Date2003
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
CitationHuman Molecular Genetics, 2003, v. 12 n. 10, p. 1131-1143 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddg124
AbstractTriglyceride (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.
ISSN0964-6906
2011 Impact Factor: 7.636
2011 SCImago Journal Rankings: 1.308
DOIhttp://dx.doi.org/10.1093/hmg/ddg124
ISI Accession Number IDWOS:000182950200006
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorWen, XY
dc.contributor.authorHegele, RA
dc.contributor.authorWang, J
dc.contributor.authorYan Wang, D
dc.contributor.authorCheung, J
dc.contributor.authorWilson, M
dc.contributor.authorYahyapour, M
dc.contributor.authorBai, Y
dc.contributor.authorZhuang, L
dc.contributor.authorSkaug, J
dc.contributor.authorYoung, TK
dc.contributor.authorConnelly, PW
dc.contributor.authorKoop, BF
dc.contributor.authorTsui, LC
dc.contributor.authorStewart, AK
dc.date.accessioned2007-09-12T03:52:26Z
dc.date.available2007-09-12T03:52:26Z
dc.date.issued2003
dc.description.abstractTriglyceride (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.
dc.description.naturelink_to_OA_fulltext
dc.identifier.citationHuman Molecular Genetics, 2003, v. 12 n. 10, p. 1131-1143 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddg124
dc.identifier.doihttp://dx.doi.org/10.1093/hmg/ddg124
dc.identifier.epage1143
dc.identifier.isiWOS:000182950200006
dc.identifier.issn0964-6906
2011 Impact Factor: 7.636
2011 SCImago Journal Rankings: 1.308
dc.identifier.issue10
dc.identifier.openurl
dc.identifier.pmid12719377
dc.identifier.scopuseid_2-s2.0-12444333161
dc.identifier.spage1131
dc.identifier.urihttp://hdl.handle.net/10722/44381
dc.identifier.volume12
dc.languageeng
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
dc.publisher.placeUnited Kingdom
dc.relation.ispartofHuman Molecular Genetics
dc.relation.referencesReferences in Scopus
dc.subject.meshAmino acid sequence
dc.subject.meshHyperlipidemia - genetics - metabolism
dc.subject.meshHypertriglyceridemia - enzymology - genetics
dc.subject.meshLipase - genetics - metabolism
dc.subject.meshLiver - pathology
dc.titleIdentification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong
  2. McLaughlin Centre for Molecular Medicine
  3. Saint Michael's Hospital, Toronto
  4. Robarts Research Institute
  5. Toronto General Hospital
  6. University of Victoria
  7. University of Toronto
  8. Hospital for Sick Children, Toronto