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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, XY5 3
Hegele, RA4
Wang, J4
Yan Wang, D5
Cheung, J8
Wilson, M6
Yahyapour, M5
Bai, Y5
Zhuang, L5
Skaug, J8
Young, TK7
Connelly, PW2
Koop, BF6
Tsui, LC8 1
Stewart, AK5 3
 
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
2013 Impact Factor: 6.677
 
DOIhttp://dx.doi.org/10.1093/hmg/ddg124
 
ISI Accession Number IDWOS:000182950200006
 
ReferencesReferences in Scopus
 
DC FieldValue
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
2013 Impact Factor: 6.677
 
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
 
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Author Affiliations
  1. The University of Hong Kong
  2. Saint Michael's Hospital University of Toronto
  3. McLaughlin Centre for Molecular Medicine
  4. Robarts Research Institute
  5. Toronto General Hospital
  6. University of Victoria
  7. University of Toronto
  8. Hospital for Sick Children University of Toronto