title: Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.
abstract: BACKGROUND
  Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential.
  
  
  METHODS
  We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG.
  
  
  RESULTS
  Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%).
  
  
  CONCLUSIONS
  In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.
authors.affiliation: Progenika Biopharma, Bizkaia, Spain. Electronic address: rute.rodrigues@grifols.com.
authors.forename: Rute
authors.initials: R
authors.lastname: Rodrigues
authors.affiliation: Progenika Biopharma, Bizkaia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Artieda
authors.affiliation: Progenika Biopharma, Bizkaia, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Tejedor
authors.affiliation: Progenika Biopharma, Bizkaia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Martínez
authors.affiliation: uniQure NV, Amsterdam, The Netherlands.
authors.forename: Pavlina
authors.initials: P
authors.lastname: Konstantinova
authors.affiliation: uniQure NV, Amsterdam, The Netherlands.
authors.forename: Harald
authors.initials: H
authors.lastname: Petry
authors.affiliation: uniQure NV, Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
authors.affiliation: uniQure NV, Amsterdam, The Netherlands.
authors.forename: Deyanira
authors.initials: D
authors.lastname: Corzo
authors.affiliation: uniQure NV, Amsterdam, The Netherlands.
authors.forename: Claus
authors.initials: C
authors.lastname: Sundgreen
authors.affiliation: Director of the German HITRIG, Third Medical Department and Policlinic, Giessen University Hospital, Justus-Liebig-University of Giessen, Giessen, Germany.
authors.forename: Hans U
authors.initials: HU
authors.lastname: Klor
authors.affiliation: Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Gouni-Berthold
authors.affiliation: Institute of Clinical Chemistry, Lipid Clinic, Magdeburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Westphal
authors.affiliation: Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steinhagen-Thiessen
authors.affiliation: Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Medizinische Klinik III, Dresden, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Julius
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine and Lipid Outpatient Clinic, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Winkler
authors.affiliation: Department of Vascular Medicine, Amsterdam Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Stroes
authors.affiliation: LMU Klinikum der Universität München, Medizinische Klinik und Poliklinik 4, München, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Vogt
authors.affiliation: Gießen and Marburg University Hospital, Giessen, Germany.
authors.forename: Phillip
authors.initials: P
authors.lastname: Hardt
authors.affiliation: Lipidambulanz, Rostock, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Prophet
authors.affiliation: Universitätsklinikum Münster, Medizinische Klinik D, Med. Clinic, Münster, Münster, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Otte
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Borge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Department of Medicine (Division of Medical Genetics), University of Washington, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Samir S
authors.initials: SS
authors.lastname: Deeb
authors.affiliation: Department of Medicine (Division of Metabolism, Endocrinology and Nutrition), University of Washington, Seattle, WA, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Brunzell
mesh_terms: D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000150:complications / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000150:complications; D008071:Lipoprotein Lipase / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D008071:Lipoprotein Lipase
keywords: Dyslipidemias; Genetics and mutation classification system; Lipase/lipoprotein deficiency; Lipoproteins/metabolism; Microarrays; Severe hypertriglyceridemia