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

TitleIdentification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humans
Authors
Issue Date2003
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2003, v. 12 n. 10, p. 1131-1143 How to Cite?
Abstract
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.
Persistent Identifierhttp://hdl.handle.net/10722/44381
ISSN
2013 Impact Factor: 6.677
ISI Accession Number ID
References

 

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
DC FieldValueLanguage
dc.contributor.authorWen, XYen_HK
dc.contributor.authorHegele, RAen_HK
dc.contributor.authorWang, Jen_HK
dc.contributor.authorYan Wang, Den_HK
dc.contributor.authorCheung, Jen_HK
dc.contributor.authorWilson, Men_HK
dc.contributor.authorYahyapour, Men_HK
dc.contributor.authorBai, Yen_HK
dc.contributor.authorZhuang, Len_HK
dc.contributor.authorSkaug, Jen_HK
dc.contributor.authorYoung, TKen_HK
dc.contributor.authorConnelly, PWen_HK
dc.contributor.authorKoop, BFen_HK
dc.contributor.authorTsui, LCen_HK
dc.contributor.authorStewart, AKen_HK
dc.date.accessioned2007-09-12T03:52:26Z-
dc.date.available2007-09-12T03:52:26Z-
dc.date.issued2003en_HK
dc.identifier.citationHuman Molecular Genetics, 2003, v. 12 n. 10, p. 1131-1143en_HK
dc.identifier.issn0964-6906en_HK
dc.identifier.urihttp://hdl.handle.net/10722/44381-
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.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_HK
dc.relation.ispartofHuman Molecular Geneticsen_HK
dc.subject.meshAmino acid sequenceen_HK
dc.subject.meshHyperlipidemia - genetics - metabolismen_HK
dc.subject.meshHypertriglyceridemia - enzymology - geneticsen_HK
dc.subject.meshLipase - genetics - metabolismen_HK
dc.subject.meshLiver - pathologyen_HK
dc.titleIdentification of a novel lipase gene mutated in lpd mice with hypertriglyceridemia and associated with dyslipidemia in humansen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0964-6906&volume=12&issue=10&spage=1131&epage=1143&date=2003&atitle=Identification+of+a+novel+lipase+gene+mutated+in+lpd+mice+with+hypertriglyceridemia+and+associated+with+dyslipidemia+in+humansen_HK
dc.identifier.emailTsui, LC: tsuilc@hkucc.hku.hken_HK
dc.identifier.authorityTsui, LC=rp00058en_HK
dc.description.naturelink_to_OA_fulltexten_HK
dc.identifier.doi10.1093/hmg/ddg124en_HK
dc.identifier.pmid12719377en_HK
dc.identifier.scopuseid_2-s2.0-12444333161en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-12444333161&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume12en_HK
dc.identifier.issue10en_HK
dc.identifier.spage1131en_HK
dc.identifier.epage1143en_HK
dc.identifier.isiWOS:000182950200006-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridWen, XY=7201737916en_HK
dc.identifier.scopusauthoridHegele, RA=35399481100en_HK
dc.identifier.scopusauthoridWang, J=36078145500en_HK
dc.identifier.scopusauthoridYan Wang, D=6505678916en_HK
dc.identifier.scopusauthoridCheung, J=7202072292en_HK
dc.identifier.scopusauthoridWilson, M=7408666439en_HK
dc.identifier.scopusauthoridYahyapour, M=6504789711en_HK
dc.identifier.scopusauthoridBai, Y=7402572426en_HK
dc.identifier.scopusauthoridZhuang, L=7102368271en_HK
dc.identifier.scopusauthoridSkaug, J=6603258009en_HK
dc.identifier.scopusauthoridYoung, TK=7403037718en_HK
dc.identifier.scopusauthoridConnelly, PW=16738577100en_HK
dc.identifier.scopusauthoridKoop, BF=7006161280en_HK
dc.identifier.scopusauthoridTsui, LC=7102754167en_HK
dc.identifier.scopusauthoridStewart, AK=7403496983en_HK

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