Factor V And Factor Viii, Combined Deficiency Of, 2

A number sign (#) is used with this entry because combined deficiency of factor V and factor VIII type 2 (F5F8D2) is caused by homozygous mutation in the MCFD2 gene (607788) on chromosome 2p.

For a general phenotypic description and a discussion of genetic heterogeneity of F5F8D, see 227300.

Description

Combined deficiency of factor V (612309) and factor VIII (300841) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (summary by Zhang and Ginsburg, 2004).

Clinical Features

Oeri et al. (1954) presented relatively convincing laboratory data for the existence of a combined deficiency of factors V and VIII. Affected patients demonstrated a moderate bleeding tendency in association with plasma levels of FV and FVIII between 5% and 30%.

Mapping

To identify a gene mutant in families whose combined deficiency of factor V and factor VIII was not caused by a defect in mannose-binding lectin-1 (LMAN1; 601567) on chromosome 18, Zhang et al. (2003) performed whole-genome linkage analysis by homozygosity mapping and identified a region on 2p21-p16.3 linked to F5F8D in non-LMAN1-linked families.

Molecular Genetics

Zhang et al. (2003) found that inactivating mutations in the MCFD2 gene (607788.0001-607788.0007) cause F5F8D with a phenotype indistinguishable from that caused by mutations in the LMAN1 gene. MCFD2 is localized to the ER-Golgi intermediate compartment (ERGIC) through a direct, calcium-dependent interaction with LMAN1. These findings suggested that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.

Combined with their previous reports, Zhang et al. (2006) had identified LMAN1 or MCFD2 mutations as the cause of F5F8D in 71 of 76 families. Among the 5 families in which no mutation was identified, 3 were due to misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2 mutations that were missed by direct sequencing. Thus, mutations in one or the other of these genes 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 or MCFD2, suggesting that complete loss of the complex may not be required for clinically significant reduction in factor V and factor VIII.

Zhang et al. (2008) identified 4 different homozygous MCFD2 mutations (see, e.g., 607788.0008) in affected members of 4 families with the disorder. These families were of Greek, Afro-Caribbean, Saudi Arabian, and Italian descent.

Genotype/Phenotype Correlations

By reviewing available published data on 46 patients with MCFD2 mutations and 96 patients with LMAN1 mutations, Zhang et al. (2008) found that patients with MCFD2 mutations had lower levels of both FV and FVIII compared to those with LMAN1 mutations. Decreased plasma values for both factors were correlated for each patient, suggesting that deficiencies in LMAN1 or MCFD2 exert a similar impact on FV and FVIII. In addition, platelet factor V levels were reduced to the same extent as plasma factor V. Zhang et al. (2008) suggested that MCFD2 plays a primary role in the export of FV and FVIII from the endoplasmic reticulum, whereas LMAN1 plays an indirect role through its interaction with MCFD2.