Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2

Zhou, Bin; McGee, Beth; Yamaoka, Jennifer S.; Guglielmone, Hugo; Downes, Katharine A.; Minoldo, Salvador; Jarchum, Gustavo; Peyvandi, Flora; Bosch, Norma B. de; Ruiz-Sáez, Arlette; Châtelain, Bernard; Olpinski, Marian; Bockenstedt, Paula; Sperl, Wolfgang; Kaufman, Randal J.; Nichols, William C.; Tuddenham, Edward G. D.; Ginsburg, David

doi:10.1182/blood-2005-09-3620

Cited by 114 publications

(130 citation statements)

References 23 publications

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“…So far, only two missense mutations have been reported in LMAN1, p.Met1Thr, and p.Cys475Arg, which resulted in little or no LMAN1 protein in the cells [13,15]. In this report, we showed that lymphoblasts from a patient with a homozygous p.Trp67Ser mutation possessed a variant LMAN1 protein in the same amount as LMAN1 in lymphoblasts from a normal individual.…”

Section: Discussionsupporting

confidence: 51%

A novel missense mutation causing abnormal LMAN1 in a Japanese patient with combined deficiency of factor V and factor VIII

et al. 2009

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Combined deficiency of coagulation factor V (FV) and factor VIII (FVIII) (F5F8D) is an inherited bleeding disorder characterized by a reduction in plasma concentrations of FV and FVIII. F5F8D is genetically linked to mutations in either LMAN1 or MCFD2. Here, we investigated the molecular basis of F5F8D in a Japanese patient, and identified a novel missense mutation (p.Trp67Ser, c.200G>C) in the LMAN1, but no mutation in the MCFD2. The amount of LMAN1 in Epstein-Barr virus-immortalized lymphoblasts from the patient was found to be almost the same as that in cells from a normal individual. Interestingly, an anti-MCFD2 antibody did not co-immunoprecipitate the mutant LMAN1 with MCFD2 in lymphoblasts from the patient, suggesting the affinity of MCFD2 for the mutant LMAN1 is weak or abolished by the binding of the anti-MCFD2 antibody. In addition, a Myc/63His-tagged recombinant form of wild-type LMAN1 could bind to D-mannose, but that of the mutant could not. The p.Trp67Ser mutation was located in the carbohydrate recognition domain (CRD), which is thought to participate in the selective binding of LMAN1 to the D-mannose of glycoproteins as well as the EF-motif of MCFD2. Taken together, it was suggested that the p.Trp67Ser mutation might affect the molecular chaperone function of LMAN1, impairing affinity for D-mannose as well as for MCFD2, which may be responsible for F5F8D in the patient. This is the first report of F5F8D caused by a qualitative defect of LMAN1 due to a missense mutation in LMAN1. Am. J. Hematol. 84:738-742, 2009. V V C 2009 WileyLiss, Inc. IntroductionCoagulation factor V (FV) and factor VIII (FVIII) are both essential in the blood coagulation cascade, as cofactors for the proteases factor X and factor IX, respectively. Combined deficiency of FV and FVIII (F5F8D) is an autosomal recessive bleeding disorder first described by Oeri et al. in 1954 [1], and a distinct clinical entity from chance co-inheritance of hemophilia A (FVIII deficiency) and parahemophilia (FV deficiency). F5F8D is extremely rare (1:2,000,000) in the general population [2], and characterized by a mild-to-moderate bleeding tendency manifested after surgical trauma, abortion, and delivery. Menorrhagia is also common, but hematuria and gastrointestinal bleeding are infrequent, and hemarthrosis is rare [3]. Generally, patients with F5F8D show plasma levels of FV and FVIII in the range of 5-30% of normal [4].Positional cloning has identified two genes, LMAN1 (lectin, mannose-binding, 1; also known as ERGIC-53) and MCFD2 (multiple coagulation factor deficiency gene 2), associated with F5F8D [4,5] LMAN1 is a Type-1 transmembrane protein that cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC) [6,7]. It contains a mannose-specific carbohydrate recognition domain (CRD) on the ER luminal side, and ER exit and retrieval motifs on the cytoplasmic side [8]. MCFD2 has an EF-hand domain that interacts with LMAN1 in a Ca 21 -dependent manner [5]. The LMAN1-MCFD2 protein complex functions as a cargo ...

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Section: Discussionsupporting

confidence: 51%

A novel missense mutation causing abnormal LMAN1 in a Japanese patient with combined deficiency of factor V and factor VIII

et al. 2009

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“…Genetic mutations in LMAN1 account for approximately 70% of F5F8D families, whereas the remaining 30% families possess mutation in MCFD2 (3,4). LMAN1 encodes the transmembrane lectin ERGIC-53 (ER-Golgi intermediate compound protein of 53 kDa) (5), which possesses a luminal carbohydrate recognition domain (CRD) with specificity for highmannose-type oligosaccharides (6,7) and forms dimers or hexamers stabilized by disulfide bonds formed in its stalk domain (5,8).…”

mentioning

confidence: 99%

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

Nishio

Kamiya

Mizushima

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Combined deficiency of coagulation factors V and VIII (F5F8D), an autosomal recessive disorder characterized by coordinate reduction in the plasma levels of factor V (FV) and factor VIII (FVIII), is genetically linked to mutations in the transmembrane lectin ERGIC-53 and the soluble calcium-binding protein MCFD2. Growing evidence indicates that these two proteins form a complex recycling between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment and thereby function as a cargo receptor in the early secretory pathway of FV and FVIII. For better understanding of the mechanisms underlying the functional coordination of ERGIC-53 and MCFD2, we herein characterize their interaction by x-ray crystallographic analysis in conjunction with NMR and ultracentrifugation analyses. Inspection of the combined data reveals that ERGIC-53-CRD binds MCFD2 through its molecular surface remote from the sugar-binding site, giving rise to a 1∶1 complex in solution. The interaction is independent of sugarbinding of ERGIC-53 and involves most of the missense mutation sites of MCFD2 so far reported in F5F8D. Comparison with the previously reported uncomplexed structure of each protein indicates that MCFD2 but not ERGIC-53-CRD undergoes significant conformational alterations upon complex formation. Our findings provide a structural basis for the cooperative interplay between ERGIC-53 and MCFD2 in capturing FV and FVIII.MCFD2 | ERGIC-53 | calcium-binding protein | cargo receptor | intracellular lectin C ombined deficiency of coagulation factors V and VIII (F5F8D) is an autosomal recessive disorder characterized by coordinate reduction in the plasma levels of factor V (FV) and factor VIII (FVIII) (1, 2) Extensive genetic analysis of F5F8D patients identified two genes that are associated with this disorder. Genetic mutations in LMAN1 account for approximately 70% of F5F8D families, whereas the remaining 30% families possess mutation in MCFD2 (3, 4). LMAN1 encodes the transmembrane lectin ERGIC-53 (ER-Golgi intermediate compound protein of 53 kDa) (5), which possesses a luminal carbohydrate recognition domain (CRD) with specificity for highmannose-type oligosaccharides (6, 7) and forms dimers or hexamers stabilized by disulfide bonds formed in its stalk domain (5, 8). By contrast, the product of MCFD2 is a soluble luminal protein with two EF-hand Ca 2þ -binding motifs (9). It has been shown that MCFD2 interacts with the CRD of ERGIC-53 in a Ca 2þ -dependent manner (9-11). Accumulating evidence indicates that this complex recycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC) and thereby functions as a cargo receptor in the early secretory pathway of FV and FVIII (12).To gain a better understanding of the molecular mechanisms underlying the sorting and trafficking of these coagulation factors, it is essential to shed light on the structural basis of the cooperative interplay between ERGIC-53 and MCFD2. The crystallographic data of the CRD of rat ERGIC-53 have revealed that it com...

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“…Whereas the above disorders affect the sorting signal on the cargo, proteins acting as cargo receptors are defective in a bleeding syndrome, combined deficiency of coagulation factors V and VIII. In this, the inclusion of the two coagulation factors into ER-Golgi carriers, and thus their secretion, is hampered by defects in ERGIC-53, a mannose-binding lectin that executes a cargo-sorting function in ER-to-Golgi trafficking (Nichols et al, 1998), or its binding partner, multiple coagulation factor deficiency protein 2 (MCFD2) (Zhang et al, 2003;Zhang et al, 2006). The patients have normal plasma concentrations of other proteins, which suggests that the Ca 2+ -dependent ERGIC-53-MCFD2 complex has a specific function in sorting of a subgroup of glycoproteins that are transported out of the ER (Zhang et al, 2005).…”

Section: Journal Of Cell Science 119 (24)mentioning

confidence: 99%

When intracellular logistics fails - genetic defects in membrane trafficking

Olkkonen

Ikonen

2006

Journal of Cell Science

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The number of human genetic disorders shown to be due to defects in membrane trafficking has greatly increased during the past five years. Defects have been identified in components involved in sorting of cargo into transport carriers, vesicle budding and scission, movement of vesicles along cytoskeletal tracks, as well as in vesicle tethering, docking and fusion at the target membrane. The nervous system is extremely sensitive to such disturbances of the membrane trafficking machinery, and the majority of these disorders display neurological defects - particularly diseases affecting the motility of transport carriers along cytoskeletal tracks. In several disorders, defects in a component that represents a fundamental part of the trafficking machinery fail to cause global transport defects but result in symptoms limited to specific cell types and transport events; this apparently reflects the redundancy of the transport apparatus. In groups of closely related diseases such as Hermansky-Pudlak and Griscelli syndromes, identification of the underlying gene defects has revealed groups of genes in which mutations lead to similar phenotypic consequences. New functionally linked trafficking components and regulatory mechanisms have thus been discovered. Studies of the gene defects in trafficking disorders therefore not only open avenues for new therapeutic approaches but also significantly contribute to our knowledge of the fundamental mechanisms of intracellular membrane transport.

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Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2

Cited by 114 publications

References 23 publications

A novel missense mutation causing abnormal LMAN1 in a Japanese patient with combined deficiency of factor V and factor VIII

A novel missense mutation causing abnormal LMAN1 in a Japanese patient with combined deficiency of factor V and factor VIII

Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency

When intracellular logistics fails - genetic defects in membrane trafficking

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