What is the genetic cause of C1 esterase deficiency?

Genetic Cause of C1 Esterase Inhibitor Deficiency

Hereditary angioedema (HAE) is caused by mutations in the SERPING1 gene, which encodes the C1 esterase inhibitor (C1INH) protein, resulting in either reduced protein levels (Type I) or normal but dysfunctional protein (Type II). 1, 2

Types of C1INH Deficiency and Their Genetic Basis

Type I HAE (85% of cases)

• Caused by various mutations in the SERPING1 gene
• Results in reduced synthesis and low plasma levels of C1INH protein
• Characterized by low antigenic C1INH levels in blood tests 1

Type II HAE (15% of cases)

• Caused by specific mutations in the SERPING1 gene, typically involving residues at or near the active site on the reactive mobile loop
• Results in normal production but dysfunctional C1INH protein
• Characterized by normal antigenic but decreased functional C1INH levels 1

HAE with Normal C1INH (formerly Type III)

• Not related to SERPING1 mutations
• Some cases associated with factor XII mutations (approximately 30% of cases)
• Other cases may involve mutations in genes related to kinin-forming enzymes, kininases, or bradykinin receptors 1, 2

Molecular Genetics of SERPING1

• SERPING1 gene encodes C1INH, a member of the serpin (serine protease inhibitor) superfamily
• The gene consists of 8 exons and produces a protein of 478 amino acids plus a 22-residue signal peptide
• C1INH protein has two domains:
  • N-terminal domain (first 100 amino acids) containing most carbohydrate attachments
  • C-terminal domain (378 amino acids) containing the active site in a stressed loop conformation 1, 3

Mutation Spectrum

• Extreme allelic heterogeneity with almost each family carrying their own unique mutation
• Over 500 different mutations have been identified in the SERPING1 gene
• Mutations include:
  • Missense mutations
  • Nonsense mutations
  • Frameshift mutations
  • Large deletions or insertions
  • Splice site mutations 3, 4

Inheritance Pattern

• Autosomal dominant inheritance pattern
• Approximately 75% of cases are inherited
• About 25% represent de novo mutations (no family history) 5, 3

Acquired C1INH Deficiency (Different from Hereditary)

It's important to distinguish hereditary from acquired C1INH deficiency:

• Acquired C1INH deficiency is not caused by SERPING1 mutations
• Instead, it results from increased catabolism of C1INH that exceeds production
• Often associated with:
  • Lymphoproliferative disorders
  • Autoantibodies against C1INH
• Distinguished from HAE by onset in middle age, absence of family history, and low C1q levels 1, 6

Clinical Implications of Genetic Testing

• Molecular genetic analysis confirms clinical diagnosis
• Allows early identification of mutation carriers before clinical manifestation
• Enables appropriate prophylactic and acute treatment strategies
• Particularly valuable for family members of affected individuals 3

Future Therapeutic Approaches

Gene therapy approaches targeting the underlying genetic defect are being investigated:

• AAV-based gene transfer vectors expressing normal human C1INH have shown promise in mouse models
• CRISPR/Cas9 technology may offer potential for genetic correction 7

Understanding the genetic basis of C1INH deficiency is crucial for accurate diagnosis, appropriate management, and development of targeted therapies for this potentially life-threatening condition.