CFHR1 – Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy driven by dysregulation of the alternative complement pathway. Homozygous deletions of CFHR1 (HGNC:4888) and CFHR3 predispose to a distinct DEAP‐HUS subtype characterized by autoantibody‐mediated inhibition of factor H (PMID:18006700). Complement factor H–related protein 1 (FHR-1) normally competes with factor H for C3b binding, and its deficiency unmasks neoepitopes in factor H that trigger pathogenic autoantibodies.

In a cohort of 147 unrelated aHUS patients, 16 (11%) had complete CFHR1/CFHR3 deficiency and high‐titer factor H autoantibodies, establishing genetic predisposition (PMID:18006700). Deletion of CFHR1 and CFHR3 was further confirmed as a risk factor in two independent cohorts (n=84; 67% with anti–factor H antibodies) and was absent in healthy controls (PMID:17367211, PMID:23243267).

Rare coding variants in CFHR1 have been identified by gene conversion events. Nine unrelated adult patients carried CFHR1 mutations c.887C>T (p.Ala296Val) and c.869T>C (p.Leu290Ser), converting FHR-1 into a potent competitor of factor H; none were detected by standard NGS but were revealed by MLPA and functional assays (PMID:28993505).

Structural rearrangements generating CFH::CFHR1 hybrid genes have been reported in multigenerational pedigrees. A CFH::CFHR1 fusion segregated in three affected relatives across three generations, demonstrating cosegregation with aHUS without alternate triggers (PMID:38524137).

Functional studies show that FHR1 variants and isoforms modulate complement regulation. The p.Ala296Val mutant FHR-1 protein impairs factor H binding to endothelial surfaces and enhances C5b-9 deposition, while the CFHR1*B isoform shows increased C3b binding and monocyte activation compared with CFHR1*A (PMID:28993505, PMID:35126388). These concordant assays elucidate a haploinsufficiency mechanism exacerbated by dominant‐negative competition.

Overall, genetic and functional evidence supports a Strong association between CFHR1 deficiency or mutation and aHUS. CFHR1 testing, including CNV analysis and sequencing for conversion events, is clinically actionable for diagnosis, risk stratification, and therapeutic decision‐making. Key Take-home: CFHR1 loss or mutation underlies complement dysregulation in aHUS and informs personalized immunosuppressive or complement inhibitor therapy.

References

• Blood • 2008 • Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency PMID:18006700
• PLoS genetics • 2007 • Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome PMID:17367211
• Clinical journal of the American Society of Nephrology • 2013 • Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome PMID:23243267
• Journal of the American Society of Nephrology • 2018 • Factor H Competitor Generated by Gene Conversion Events Associates with Atypical Hemolytic Uremic Syndrome PMID:28993505
• Frontiers in immunology • 2022 • Atypical Hemolytic Uremic Syndrome-Associated FHR1 Isoform FHR1*B Enhances Complement Activation and Inflammation PMID:35126388
• Frontiers in immunology • 2024 • Case report: A family of atypical hemolytic uremic syndrome involving a CFH::CFHR1 fusion gene and CFHR3-1-4-2 gene duplication PMID:38524137

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