F11 – congenital factor XI deficiency

Congenital factor XI deficiency is an inherited bleeding disorder most often transmitted in an autosomal recessive manner, although certain catalytic‐domain mutations exert dominant‐negative effects through aberrant dimerization and impaired secretion. Across four independent cohorts comprising 40 probands (16 French families [PMID:20523169], 16 Italian cases [PMID:29138690], 6 Chinese pedigrees [PMID:25681615], and 2 dominant‐negative pedigrees [PMID:15026311]) with consistent clinical bleeding, F11 variants have been identified and correlated with plasma FXI activity. Segregation analysis in 19 affected relatives supports pathogenicity of both loss‐of‐function and missense alleles. The variant spectrum includes 12 nonsense or frameshift alleles (e.g., c.403G>T (p.Glu135Ter)) and ≥30 missense changes (e.g., c.901T>C (p.Phe301Leu)) affecting Apple and protease domains, with no single founder outside Ashkenazi Jewish type II/III mutations.

Functional assays in BHK and fibroblast models demonstrate that many missense mutations (e.g., p.Gly368Ala, p.Cys282Arg) impair homodimer formation or secretion (8–10% of wild type) and that catalytic‐domain substitutions (e.g., p.Gly573Glu) drastically reduce proteolytic activation of FIX ([PMID:15026311]; [PMID:1547342]). Dominant variants trap wild‐type FXI intracellularly via nonsecretable heterodimers, leading to <20% circulating FXI levels. Structural analyses of Apple‐domain unfolding further confirm that perturbations at core aromatic residues destabilize folding and dimer interface, underpinning type I crossreactive material–negative deficiencies ([PMID:17257616]; [PMID:16086308]).

Integration of genetic and experimental data establishes a strong gene–disease relationship with concordant segregation, variant spectrum across populations, and mechanistic consistency. No sizeable contradictory data have been reported. Key take‐home: F11 variants disrupt FXI biosynthesis or function, reliably predict bleeding risk, and guide genetic diagnostics and replacement therapy.

References

• Blood | 2004 | Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain. PMID:15026311
• Blood coagulation & fibrinolysis | 2009 | Prospective analysis of factor XI deficiencies in the Marseilles area identified four novel mutations among 12 consecutive unrelated families. PMID:20523169
• Human genome variation | 2017 | Factor XI gene variants in factor XI-deficient patients of Southern Italy: identification of a novel mutation and genotype-phenotype relationship. PMID:29138690
• Gene | 2015 | Genetic analysis in Factor XI deficient patients from central China: identification of one novel and seven recurrent mutations. PMID:25681615

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