Genetic analysis of C4 deficiency

Area of Science:

• Immunogenetics
• Complement System Biology
• Molecular Immunology

Background:

• The fourth component of complement (C4) exists in several structural forms, influencing its function and serum levels.
• Polymorphisms in C4 genes can lead to deficiencies or altered protein expression, with implications for immune response.
• Understanding C4 gene structure and expression is crucial for diagnosing and managing complement-related disorders.

Purpose of the Study:

• To investigate the inherited structural polymorphism of the fourth component of complement (C4) within a family.
• To determine the genetic basis for homozygous C4 deficiency in a child.
• To correlate C4 gene copy number with serum C4 protein levels in family members.

Main Methods:

• Family-based genetic analysis of C4 structural polymorphism.
• Detection of C4 haplotypes, including null variants (C4A*QO, C4B*QO).
• Quantification of serum C4 levels and correlation with the number of expressed C4 genes.

Main Results:

• Identified a C4 haplotype (C4A*QO C4B*QO) in family members that resulted in undetectable Chido (C4B) and Rodgers (C4A) antigens.
• Documented individuals with varying numbers of expressed C4 genes (one to four).
• Demonstrated a positive correlation between the number of expressed C4 genes and mean serum C4 levels.

Conclusions:

• Inherited C4 structural polymorphism, specifically null haplotypes, can cause undetectable C4 protein.
• The number of expressed C4 genes is a significant determinant of serum C4 levels.
• This study elucidates the genetic basis of C4 deficiency and its impact on complement component levels within a family.