Molecular basis of antithrombin deficiency

Area of Science:

• * Coagulation and Thrombosis
• * Molecular Genetics
• * Rare Disease Pathogenesis

Background:

• * Antithrombin (AT) is a key inhibitor of coagulation proteases, crucial for preventing blood clots.
• * Hereditary AT deficiency is a rare genetic disorder primarily associated with an increased risk of venous thromboembolism.
• * Over 200 mutations in the antithrombin gene (SERPINC1) have been identified, contributing to diverse molecular backgrounds.

Purpose of the Study:

• * To characterize the molecular basis of antithrombin deficiency in a large patient cohort.
• * To identify and classify SERPINC1 gene mutations.
• * To predict the functional impact of novel mutations on AT function and deficiency pathogenesis.

Main Methods:

• * Direct sequencing of the SERPINC1 gene in 272 patients with AT deficiency.
• * Multiplex PCR, liquid chromatography, and MLPA for detecting large deletions.
• * In silico assessments, multiple sequence alignment, and molecular graphic imaging to predict mutation effects.

Main Results:

• * Identified 87 distinct SERPINC1 mutations in 272 patients, with 42 being novel (22 missense, 20 null).
• * The mutation spectrum included 59% missense, 10% nonsense, 8% splice site, 15% small indels, and 8% large deletions.
• * Nine novel missense mutations potentially impair AT activation, two affect critical functional sites, and six impact structural integrity.

Conclusions:

• * Characterizing the SERPINC1 mutation profile in large cohorts is essential for understanding AT deficiency.
• * The study identified numerous novel mutations, expanding the known genetic landscape of hereditary antithrombin deficiency.
• * Further genotype-phenotype correlation studies are needed to fully elucidate the pathogenesis and clinical implications.