title: Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia.
abstract: Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL), caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER). Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia.
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. mpeterfy@ucla.edu
authors.forename: Miklós
authors.initials: M
authors.lastname: Péterfy
authors.forename: Osnat
authors.initials: O
authors.lastname: Ben-Zeev
authors.forename: Hui Z
authors.initials: HZ
authors.lastname: Mao
authors.forename: Daphna
authors.initials: D
authors.lastname: Weissglas-Volkov
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Aouizerat
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.forename: Philip H
authors.initials: PH
authors.lastname: Frost
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Malloy
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.forename: Mark H
authors.initials: MH
authors.lastname: Doolittle
mesh_terms: D000818:Animals; D018389:Codon, Nonsense; D004721:Endoplasmic Reticulum; D020022:Genetic Predisposition to Disease; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D017434:Protein Structure, Tertiary
chemical_list: D018389:Codon, Nonsense; D008071:Lipoprotein Lipase