Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia.
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.
Péterfy
Miklós
M
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. mpeterfy@ucla.edu
Ben-Zeev
Osnat
O
Mao
Hui Z
HZ
Weissglas-Volkov
Daphna
D
Aouizerat
Bradley E
BE
Pullinger
Clive R
CR
Frost
Philip H
PH
Kane
John P
JP
Malloy
Mary J
MJ
Reue
Karen
K
Pajukanta
Päivi
P
Doolittle
Mark H
MH
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
D018389:Codon, Nonsense; D008071:Lipoprotein Lipase