title: Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin.
abstract: The type 1-transmembrane protein LMAN1 (ERGIC-53) forms a complex with the soluble protein MCFD2 and cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Mutations in either LMAN1 or MCFD2 cause the combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D), suggesting an ER-to-Golgi cargo receptor function for the LMAN1-MCFD2 complex. Here we report the analysis of LMAN1-deficient mice. Levels of plasma FV and FVIII, and platelet FV, are all reduced to ∼ 50% of wild-type in Lman1(-/-) mice, compared with the 5%-30% levels typically observed in human F5F8D patients. Despite previous reports identifying cathepsin C, cathepsin Z, and α1-antitrypsin as additional potential cargoes for LMAN1, no differences were observed between wild-type and Lman1(-/-) mice in the levels of cathepsin C and cathepsin Z in liver lysates or α1-antitrypsin levels in plasma. LMAN1 deficiency had no apparent effect on COPII-coated vesicle formation in an in vitro assay. However, the ER in Lman1(-/-) hepatocytes is slightly distended, with significant accumulation of α1-antitrypsin and GRP78. An unexpected, partially penetrant, perinatal lethality was observed for Lman1(-/-) mice, dependent on the specific inbred strain genetic background, suggesting a potential role for other, as yet unidentified LMAN1-dependent cargo proteins.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Chunlei
authors.initials: C
authors.lastname: Zheng
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Jiayi
authors.initials: J
authors.lastname: Tao
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Vasievich
authors.forename: Andrea
authors.initials: A
authors.lastname: Baines
authors.forename: Jinoh
authors.initials: J
authors.lastname: Kim
authors.forename: Randy
authors.initials: R
authors.lastname: Schekman
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000818:Animals; D001692:Biological Transport; D001778:Blood Coagulation Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D022181:COP-Coated Vesicles / Q000378:metabolism; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism; D056663:Cathepsin Z / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005165:Factor V / Q000235:genetics / Q000378:metabolism*; D005166:Factor V Deficiency / Q000097:blood* / Q000235:genetics; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006056:Golgi Apparatus / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D037241:Mannose-Binding Lectins / Q000172:deficiency / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism
chemical_list: C515307:ERGIC-53 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D000515:alpha 1-Antitrypsin; D005165:Factor V; D005169:Factor VIII; D020789:Cathepsin C; D056663:Cathepsin Z