Dominant effects of mutations in the collagenous domain of mannose-binding protein

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Mannose-binding protein (MBP) deficiency, also known as mannose-binding lectin (MBL) deficiency, is linked to increased susceptibility to infections.
• Heterozygosity for mutant MBP alleles is common and associated with impaired immune responses.

Purpose of the Study:

• To investigate the molecular basis of impaired complement activation in heterozygous individuals with mutant MBP alleles.
• To elucidate how structural defects in MBP lead to functional deficiencies.

Main Methods:

• Coexpression of wild-type rat MBP and mutant rat MBP in a mammalian expression system.
• Analysis of secreted MBP heterooligomer formation and complement activation.
• Structural analysis of MBP domains to identify mutation-induced changes.

Main Results:

• Coexpressed MBP formed heterooligomers, with mutant and wild-type subunits present.
• These heterooligomers exhibited defective complement cascade activation.
• Structural alterations in the N-terminal collagenous and cysteine-rich domains of MBP were identified, impairing serine protease interactions.

Conclusions:

• The presence of a single mutant MBP allele leads to defective MBP heterooligomers.
• Structural defects in MBP disrupt complement activation, explaining the increased infection susceptibility in heterozygous individuals.
• This highlights the dominant effect of mutant alleles in disease pathogenesis.