Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin

Bin Zhang, Chunlei Zheng, Min Zhu, Jiayi Tao, Matthew P. Vasievich, Andrea Baines, Jinoh Kim, Randy Schekman, Randal J. Kaufman, David Ginsburg

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 wildtype 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 lethalitywasobserved forLman1 -/- mice, dependent on the specific inbred strain genetic background, suggesting a potential role for other, as yet unidentified LMAN1-dependent cargo proteins.

Original languageEnglish (US)
Pages (from-to)3384-3391
Number of pages8
JournalBlood
Volume118
Issue number12
DOIs
StatePublished - Sep 22 2011

Fingerprint

Factor V Deficiency
Factor V
Cathepsin Z
Cathepsin C
Endoplasmic Reticulum
Liver
Plasmas
COP-Coated Vesicles
Proteins
Factor VIII
Assays
Hepatocytes
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Zhang, B., Zheng, C., Zhu, M., Tao, J., Vasievich, M. P., Baines, A., ... Ginsburg, D. (2011). Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin. Blood, 118(12), 3384-3391. https://doi.org/10.1182/blood-2011-05-352815

Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin. / Zhang, Bin; Zheng, Chunlei; Zhu, Min; Tao, Jiayi; Vasievich, Matthew P.; Baines, Andrea; Kim, Jinoh; Schekman, Randy; Kaufman, Randal J.; Ginsburg, David.

In: Blood, Vol. 118, No. 12, 22.09.2011, p. 3384-3391.

Research output: Contribution to journalArticle

Zhang, B, Zheng, C, Zhu, M, Tao, J, Vasievich, MP, Baines, A, Kim, J, Schekman, R, Kaufman, RJ & Ginsburg, D 2011, 'Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin', Blood, vol. 118, no. 12, pp. 3384-3391. https://doi.org/10.1182/blood-2011-05-352815
Zhang, Bin ; Zheng, Chunlei ; Zhu, Min ; Tao, Jiayi ; Vasievich, Matthew P. ; Baines, Andrea ; Kim, Jinoh ; Schekman, Randy ; Kaufman, Randal J. ; Ginsburg, David. / Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin. In: Blood. 2011 ; Vol. 118, No. 12. pp. 3384-3391.
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AU - Vasievich, Matthew P.

AU - Baines, Andrea

AU - Kim, Jinoh

AU - Schekman, Randy

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