Molecular heterogeneity in deficiency of complement protein C2 type I

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Complement protein C2 deficiency (C2D) is common and linked to rheumatological issues and infections.
• Existing C2D types (I and II) are associated with specific major histocompatibility complex (MHC) haplotypes.
• Molecular heterogeneity in C2D suggests additional genetic causes beyond known types.

Purpose of the Study:

• To investigate the molecular basis of C2 deficiency in a child with recurrent infections and a unique MHC haplotype.
• To identify novel genetic mutations causing C2 deficiency.
• To analyze the impact of these mutations on C2 and Factor B (Bf) gene expression and protein levels.

Main Methods:

• Analysis of C2 protein synthesis in patient fibroblasts.
• Quantification of C2 messenger RNA (mRNA) levels.
• Nucleotide sequencing of C2 mRNA and genomic DNA using RT-PCR.
• Assessment of Factor B (Bf) gene expression and protein concentration.

Main Results:

• The child exhibited no detectable C2 protein synthesis and reduced C2 mRNA (42% of normal).
• Genetic analysis revealed a type I C2 deficiency (28 bp deletion) on one allele and a novel 2 bp deletion in exon 2 on the other.
• Factor B (Bf) gene expression was significantly decreased (mRNA 25% of normal), despite normal Bf protein levels in plasma.

Conclusions:

• This case demonstrates a previously unrecognized molecular basis for C2 deficiency, highlighting genetic heterogeneity.
• The novel mutations contribute to C2 absence and affect linked Factor B gene expression.
• Understanding this heterogeneity is crucial for diagnosing and managing C2-deficient patients with infections and autoimmune conditions.