Factor V And Factor Viii, Combined Deficiency Of, 1

A number sign (#) is used with this entry because combined deficiency of factor V and factor VIII type 1 can be caused by homozygous mutation in the mannose-binding lectin-1 gene (LMAN1; 601567) on chromosome 18.

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).

Genetic Heterogeneity of Combined Deficiency of Factor V and Factor VIII

Another form of combined deficiency of factor V and factor VII (F5F8D2; 613625) is caused by mutation in the MCFD2 gene (607788) on chromosome 2.

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%.

Nichols et al. (1997) stated that at least 89 patients with F5F8D belonging to 58 families had been identified.

Inheritance

Consanguinity in several reported families with F5F8D supported autosomal recessive inheritance (Seibert et al., 1958; Jones et al., 1962).

Smit Sibinga et al. (1972) studied an extensive family with combined F5F8D. They concluded that inheritance is most likely autosomal recessive with variable expression and partial penetrance in heterozygotes. However, Tuddenham (1997) pointed out that heterozygotes have normal factor V and factor VIII levels.

Cimo et al. (1977) reported an affected male whose parents were first cousins from the northwestern coast of Spain.

Population Genetics

Seligsohn et al. (1982) counted 26 separate reported families including those described in their report. Populations from the Mediterranean basin accounted for most cases: Spanish, Italian, Yugoslavian, Greek, Algerian, Oriental Jewish, and Sephardic Jewish. Ashkenazi Jews had not been affected. Seligsohn et al. (1982) related the difference in frequency of the disease in the 2 main branches of Jewry to historical differences in the Diaspora. The highest frequency of F5F8D was found in Jews of Sephardic and Middle Eastern origin living in Israel with an estimated frequency of 1 in 100,000.

Mapping

Nichols et al. (1997) used a positional cloning approach to identify the gene mutant in F5F8D. Of 14 affected individuals from 8 unrelated Jewish patients, 12 were offspring of first-cousin marriages. After a genomewide search using 241 highly polymorphic short tandem repeat (STR) markers, 13 of the 14 affected patients were found to be homozygous for 2 closely linked 18q markers. Patients and all available family members were genotyped for 11 additional STRs spanning approximately 11 cM on 18q. Multipoint linkage analysis yielded a maximum lod score of 13.22. Haplotype analysis identified a number of recombinant individuals and established a minimum candidate interval of 2.5 cM for the gene responsible for combined factors V and VIII deficiency. Nichols et al. (1997) commented that the product of this locus is likely to operate at a common step in the biosynthetic pathway for these 2 functionally and structurally homologous coagulation proteins. Different founder haplotypes were found in Tunisian-Jewish families and non-Tunisian-Jewish families, indicating a split between Tunisian Jews and other Jews of Sephardic and Middle Eastern origin. The extent of the complete linkage disequilibrium in the Tunisian-Jewish families was at least 6 cM and suggested that the mutation in this branch was more recent than that in the non-Tunisian families who demonstrated complete linkage disequilibrium over a smaller distance of less than 1.0 cM.

Neerman-Arbez et al. (1997) studied linkage of F5F8D in 17 Iranian families with a total of 28 affected individuals. All pedigrees except 1 contained at least 1 consanguineous marriage. The report of linkage to 18q in Jewish families (Nichols et al., 1997) led them to concentrate on markers in that region. Neerman-Arbez et al. (1997) found evidence from informative recombinants that the F5F8D locus is situated between D18S849 and D18S64 in an interval of approximately 3 cM. Thus, the investigators suggested that F5F8D is genetically homogeneous in different populations.

Molecular Genetics

Nichols et al. (1998) found that the ERGIC53 (LMAN1) gene, encoding a component of the ER-Golgi intermediate compartment, mapped to a YAC and BAC contig containing the critical region for the gene mutant in combined factors V and VIII deficiency. A DNA analysis identified 2 different mutations, accounting for all affected individuals in 9 families studied. Previous studies of 9 Sephardic Jewish and Middle Eastern Jewish families identified 2 distinct haplotypes segregating with the disease, suggesting a possibility of 2 independent founder chromosomes. Indeed, the 5 Sephardic Jewish families were found to be carrying a splice donor mutation (601567.0002), whereas 9 affected individuals in the 4 Middle Eastern Jewish families were homozygous for a G insertion (601567.0001).

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 5 different homozygous mutations in the LMAN1 gene (see, e.g., 601567.0003-601567.0005) in individuals from 6 families with combined factor V and VIII deficiency. The families were of Turkish, Iraqi, Iranian, 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.

History

Marlar and Griffin (1980) identified in normal plasma a protein inhibitor of activated protein C (PCI; 601841) and showed that this inhibitor is deficient in combined factor V and VIII deficiency. However, Sadler (1997) noted that deficiency of protein C inhibitor as the basic defect in F5F8D had been excluded on several grounds. Furthermore, Nichols et al. (1998) cited several studies documenting normal PCI levels in patients with F5F8D and demonstrating that the initial observation of decreased levels was due to a laboratory artifact.