F13A1 – Factor XIII Deficiency

Factor XIII deficiency is an autosomal recessive bleeding disorder caused by bi-allelic mutations in the F13A1 gene, encoding the catalytic A subunit of coagulation factor XIII. Affected individuals present early in life with umbilical cord bleeding, soft tissue hematomas, intracranial hemorrhage, and delayed wound healing. Due to normal routine coagulation assays, diagnosis requires specific clot solubility or antigen/activity tests and genetic confirmation. (PMID:14695539)

Genetic evidence supporting a strong association includes at least 10 unrelated probands from consanguineous and non-consanguineous pedigrees, uniformly demonstrating severe FXIII deficiency with undetectable activity. Over 50 distinct F13A1 pathogenic alleles have been identified, comprising predominantly missense substitutions in the core domain and numerous null variants (nonsense, frameshift, splice site). One recurrent founder null allele (c.1226G>A) has been described in Tunisian patients. (PMID:20037244)

Variants span all functional domains: missense mutations impair stability and dimer or tetramer assembly, while frameshift and nonsense mutations truncate the protein. A representative pathogenic frameshift allele is c.1652delC (p.Thr551LysfsTer26) identified in a homozygous proband with severe bleeding and undetectable FXIII activity. (PMID:30935919)

Segregation analyses in consanguineous families confirm autosomal recessive inheritance, with three affected siblings in a single pedigree and multiple carriers in extended kindreds. Functional assays demonstrate loss of antigen and enzymatic activity in homozygotes, with heterozygotes asymptomatic or with mild bleeding under hemostatic challenge. (PMID:1816054)

Experimental studies elucidate the mechanism of pathogenicity: missense mutations such as p.Arg260His and p.Val415Phe reduce transglutaminase activity and thermostability when expressed in yeast, impair dimer formation, and weaken heterotetramer assembly with the B subunit. Splice site and deep intronic mutations can permit partial correct splicing, explaining residual activity in milder phenotypes. (PMID:10027709; PMID:11695887; PMID:9028951)

No significant conflicting evidence has been reported. Emerging gene‐editing approaches using CRISPR/Cas9 to correct common point mutations (e.g., c.562C>T) in patient-derived fibroblasts demonstrate proof-of-concept for curative therapy. (PMID:35221320)

In summary, bi-allelic F13A1 mutations produce a definitive autosomal recessive factor XIII deficiency with severe bleeding risk. Early genetic diagnosis enables prophylactic replacement therapy and family counseling. Key Take-home: F13A1 gene sequencing should be pursued in patients with unexplained hemorrhagic diathesis to guide life-saving prophylaxis.

References

• Blood • 1997 • Molecular mechanism of a mild phenotype in coagulation factor XIII (FXIII) deficiency: a splicing mutation permitting partial correct splicing of FXIII A-subunit mRNA PMID:9028951
• Human Mutation • 2004 • Phenotype-genotype characterization of 10 families with severe A subunit factor XIII deficiency PMID:14695539
• British Journal of Haematology • 1999 • Identification and characterization of two missense mutations causing factor XIIIA deficiency PMID:10027709
• Biochemistry • 2001 • Impaired protein folding, dimer formation, and heterotetramer assembly cause intra- and extracellular instability of a Y283C mutant of the A subunit for coagulation factor XIII PMID:11695887
• Gene • 2019 • Identification of novel pathogenic F13A1 mutation and novel NBEAL2 gene missense mutation in a pedigree with hereditary congenital factor XIII deficiency PMID:30935919

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