title: Mutations in exon 3 of the lipoprotein lipase gene segregating in a family with hypertriglyceridemia, pancreatitis, and non-insulin-dependent diabetes.
abstract: A proband with chylomicronemia, pancreatitis, and non-insulin-dependent diabetes (NIDDM) bears two different mutations in exon 3 of the lipoprotein lipase (LPL) gene: a missense mutation, 75Arg-->Ser, inherited through the paternal line and a truncation, 73Tyr-->Ter, through the maternal line. NIDDM appeared to be independently segregating. The R75S mutant was studied in extracts and media from transfected COS-1 cells. Detectable amounts of catalytically competent R75S LPL suggested destabilization of the active homodimer as with exon 5 mutants (Hata et al. 1992. J. Biol. Chem. 267:20132-20139). Hydrolysis of a short-chain fatty acid ester indicated that R75S does not directly affect activation of LPL by apoC-II. Subjects with NIDDM and wild-type LPL, and nondiabetic middle-aged carriers of the 73Tyr-->Ter truncation had moderate hypertriglyceridemia (260-521 mg/dl) and reduced high density lipoprotein cholesterol. A maternal aunt with NIDDM carried the truncation. Her phenotype (triglycerides of 5,300 mg/dl, eruptive xanthomatosis, and recurrent pancreatitis) was as severe as that in homozygotes or compound heterozygotes. We conclude: (a) diabetic carriers of dysfunctional LPL alleles are at risk for severe lipemia; and (b) the physiologic defects in NIDDM may be additive or synergistic with heterozygous LPL deficiency.
authors.affiliation: Howard Hughes Medical Institute, University of Utah, Salt Lake City 84132.
authors.forename: D E
authors.initials: DE
authors.lastname: Wilson
authors.forename: A
authors.initials: A
authors.lastname: Hata
authors.forename: L K
authors.initials: LK
authors.lastname: Kwong
authors.forename: A
authors.initials: A
authors.lastname: Lingam
authors.forename: J
authors.initials: J
authors.lastname: Shuhua
authors.forename: D N
authors.initials: DN
authors.lastname: Ridinger
authors.forename: C
authors.initials: C
authors.lastname: Yeager
authors.forename: K C
authors.initials: KC
authors.lastname: Kaltenborn
authors.forename: P H
authors.initials: PH
authors.lastname: Iverius
authors.forename: J M
authors.initials: JM
authors.lastname: Lalouel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000235:genetics*; D015228:Hypertriglyceridemia / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010195:Pancreatitis / Q000235:genetics*; D010375:Pedigree
chemical_list: D009838:Oligodeoxyribonucleotides; D008071:Lipoprotein Lipase