Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2.
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.
Zhang
Bin
B
Life Sciences Institute, Department of Internal Medicine, 210 Washtenaw Ave, Ann Arbor, MI 48109-0650, USA.
McGee
Beth
B
Yamaoka
Jennifer S
JS
Guglielmone
Hugo
H
Downes
Katharine A
KA
Minoldo
Salvador
S
Jarchum
Gustavo
G
Peyvandi
Flora
F
de Bosch
Norma B
NB
Ruiz-Saez
Arlette
A
Chatelain
Bernard
B
Olpinski
Marian
M
Bockenstedt
Paula
P
Sperl
Wolfgang
W
Kaufman
Randal J
RJ
Nichols
William C
WC
Tuddenham
Edward G D
EG
Ginsburg
David
D
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
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