A complement factor B mutation in a large kindred with atypical hemolytic uremic syndrome

Area of Science:

• Genetics
• Complement System Biology
• Nephrology

Background:

• Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy.
• Gain-of-function mutations in complement factor B (CFB) are implicated in aHUS but are exceptionally uncommon.

Purpose of the Study:

• To report a large kindred with aHUS linked to a CFB mutation.
• To further characterize patients with CFB-mutated aHUS.

Main Methods:

• Pedigree analysis of a large family with aHUS.
• Genetic sequencing to identify CFB mutations.
• Complement pathway activation assessment (alternative pathway, complement component 3 levels).
• Structural analysis of the identified CFB mutation.

Main Results:

• Three members of the kindred had aHUS.
• Nine of 12 family members, including two affected patients, exhibited persistent alternative pathway activation and low complement component 3.
• A heterozygous CFB mutation (c.1050G>C, p.Lys350Asn) in exon 8 was identified in these nine individuals.
• Structural studies indicated the mutation enhances CFB function, predisposing to aHUS.
• Two of the three aHUS patients maintained normal renal function long-term.

Conclusions:

• The identified CFB mutation (c.1050G>C, p.Lys350Asn) is a cause of aHUS.
• Further research with larger patient cohorts is needed to establish phenotype-genotype correlations and understand outcomes in CFB-mutated aHUS.