A patient with C3 glomerulopathy (C3GN) undergoes genetic testing. A heterozygous gain-of-function mutation in C3 (p.Lys155Gln) is found. What is the direct consequence of this mutation on the alternative complement pathway?

• A Mutant C3 spontaneously activates without factor D, generating excess C3a
• B The mutation prevents properdin from binding C3b, abrogating convertase formation
• C Mutant C3 directly activates the terminal complement pathway independently of C5 convertase
• D The mutant C3 resists cleavage by factor I, prolonging the half-life of C3b and amplifying the alternative pathway convertase (C3bBb) ✓

Explanation

Gain-of-function mutations in C3 (such as p.Lys155Gln) cause C3 glomerulopathy by generating C3b that resists factor I-mediated inactivation to iC3b. Normally, factor I cleaves C3b (in the presence of factor H or CD46 as cofactors) to terminate complement amplification. Mutation-resistant C3b persists longer, continuously regenerates the C3bBb convertase (with factor B and factor D), and drives sustained alternative pathway activation with C3 deposition in glomeruli. This is distinct from factor H deficiency (impaired regulation of normal C3b). The mutation does not directly activate the terminal pathway.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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