title: Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2.
abstract: Mutations in LMAN1 (ERGIC-53) or MCFD2 cause combined deficiency of factor V and factor VIII (F5F8D). LMAN1 and MCFD2 form a protein complex that functions as a cargo receptor ferrying FV and FVIII from the endoplasmic reticulum to the Golgi. In this study, we analyzed 10 previously reported and 10 new F5F8D families. Mutations in the LMAN1 or MCFD2 genes accounted for 15 of these families, including 3 alleles resulting in no LMAN1 mRNA accumulation. Combined with our previous reports, we have identified LMAN1 or MCFD2 mutations as the causes of F5F8D in 71 of 76 families. Among the 5 families in which no mutations were identified, 3 were due to misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2 mutations that were missed by direct sequencing. Our results suggest that mutations in LMAN1 and MCFD2 may account for all cases of F5F8D. Immunoprecipitation and Western blot analysis detected a low level of LMAN1-MCFD2 complex in lymphoblasts derived from patients with missense mutations in LMAN1 (C475R) or MCFD2 (I136T), suggesting that complete loss of the complex may not be required for clinically significant reduction in FV and FVIII.
authors.affiliation: Life Sciences Institute, Department of Internal Medicine, 210 Washtenaw Ave, Ann Arbor, MI 48109-0650, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Beth
authors.initials: B
authors.lastname: McGee
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yamaoka
authors.forename: Hugo
authors.initials: H
authors.lastname: Guglielmone
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Downes
authors.forename: Salvador
authors.initials: S
authors.lastname: Minoldo
authors.forename: Gustavo
authors.initials: G
authors.lastname: Jarchum
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.forename: Norma B
authors.initials: NB
authors.lastname: de Bosch
authors.forename: Arlette
authors.initials: A
authors.lastname: Ruiz-Saez
authors.forename: Bernard
authors.initials: B
authors.lastname: Chatelain
authors.forename: Marian
authors.initials: M
authors.lastname: Olpinski
authors.forename: Paula
authors.initials: P
authors.lastname: Bockenstedt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: William C
authors.initials: WC
authors.lastname: Nichols
authors.forename: Edward G D
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D015153:Blotting, Western / Q000379:methods; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D005165:Factor V / Q000378:metabolism; D005166:Factor V Deficiency / Q000235:genetics* / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D006467:Hemophilia A / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D037241:Mannose-Binding Lectins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D017354:Point Mutation; D021381:Protein Transport / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; C084004:LMAN1 protein, human; C475146:MCFD2 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D033921:Vesicular Transport Proteins; D005165:Factor V; D005169:Factor VIII