MCFD2 – Combined deficiency of factor V and factor VIII

MCFD2 encodes a calcium-binding EF-hand protein that complexes with LMAN1 to form a cargo receptor mediating ER-to-Golgi transport of coagulation factors V (FV) and VIII (FVIII). Biallelic pathogenic variants in MCFD2 cause combined deficiency of FV and FVIII (F5F8D), a rare autosomal recessive bleeding disorder characterized by mild-to-moderate hemorrhagic diathesis ([PMID:16304051]).

Clinical validity. F5F8D due to MCFD2 variants follows autosomal recessive inheritance with >50 unrelated families reported across diverse populations, including founder alleles in Tunisia and India, and consistent segregation in multiple kindreds ([PMID:16304051], [PMID:18391077]). No credible conflicting reports have emerged over >15 years, supporting a Definitive gene–disease association.

Genetic evidence. More than 20 distinct MCFD2 variants (12 missense, 4 frameshift, 4 splice, 2 large deletions) have been identified in ≥60 probands from >50 families, often with homozygous or compound heterozygous genotypes and documented cosegregation in relatives. A recurrent missense founder variant c.241G>T (p.Asp81Tyr) ([PMID:18391077]) exemplifies the variant spectrum and confirms the autosomal recessive mode.

Functional evidence. MCFD2 mutants in the EF-hand domains abolish interaction with LMAN1 and destabilize the protein, as shown by immunoprecipitation, circular dichroism and NMR structural studies ([PMID:12717434], [PMID:18590741]). In vitro assays demonstrate loss of FV/FVIII binding and secretion. MCFD2-deficient mice recapitulate reduced plasma FV and FVIII levels, corroborating the pathogenic mechanism ([PMID:29735583]).

Integration & utility. The concordant genetic, biochemical and animal model data establish that loss-of-function MCFD2 variants lead to deficient ER exit of FV/FVIII, resulting in the F5F8D phenotype. Genetic testing for MCFD2 should be included in diagnostic panels for unexplained combined FV/FVIII deficiency. Carrier screening is warranted in high-risk populations with known founder alleles.

Key Take-home. Biallelic MCFD2 variants definitively cause combined factor V and VIII deficiency via cargo receptor disruption, enabling precise molecular diagnosis and informed carrier counseling.

References

• Blood • 2006 • Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. PMID:16304051
• Blood • 2008 • Genotype-phenotype correlation in combined deficiency of factor V and factor VIII. PMID:18391077
• Nature Genetics • 2003 • Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. PMID:12717434
• Journal of Molecular Biology • 2008 • New insights into multiple coagulation factor deficiency from the solution structure of human MCFD2. PMID:18590741
• Blood Advances • 2018 • Analysis of MCFD2- and LMAN1-deficient mice demonstrates distinct functions in vivo. PMID:29735583

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