The Relevance of the MCP Risk Polymorphism to the Outcome of aHUS Associated With C3 Mutations. A Case Report

Abstract

Thrombotic microangiopathy (TMA) has different etiological causes, and not all of them are well understood. In atypical hemolytic uremic syndrome (aHUS), the TMA is caused by the complement dysregulation associated with pathogenic mutations in complement components and its regulators. Here, we describe a pediatric patient with aHUS in whom the relatively benign course of the disease confused the initial diagnosis. A previously healthy 8-year-old boy developed jaundice, hematuria, hemolytic anemia, thrombopenia, and mild acute kidney injury (AKI) in the context of a diarrhea without hypertension nor oliguria. Spontaneous and complete recovery was observed from the third day of admission. Persistent low C3 plasma levels after recovery raised the suspicion for aHUS, which prompted clinicians to discard the initial diagnosis of Shigatoxin-associated HUS (STEC-HUS). A thorough genetic and molecular study of the complement revealed the presence of an isolated novel pathogenic C3 mutation. The relatively benign clinical course of the disease as well as the finding of a de novo pathogenic C3 mutation are remarkable aspects of this case. The data are discussed to illustrate the benefits of identifying the TMA etiological factor and the relevant contribution of the MCP aHUS risk polymorphism to the disease severity.

A Novel Homozygous In-Frame Deletion in Complement Factor 3 Underlies Early-Onset Autosomal Recessive Atypical Hemolytic Uremic Syndrome - Case Report

“…C3-associated aHUS is mostly attributed to heterozygous gain-of-function variants in the C3 gene, leading to unbalanced activation of the complement cascade ( 8 , 26 – 28 ). Furthermore, the presentation of aHUS in carriers of C3 gain-of-function mutations may be influenced by the presence of the MCP ggaac risk haplotype, as previously described ( 29 ). In contrast, homozygous loss-of-function variants in C3 are usually implicated in C3 deficiency, manifested by increased susceptibility to recurrent bacterial infections and autoimmunity, unrelated to aHUS ( 15 , 16 ).…”

The Rationale of Complement Blockade of the MCPggaac Haplotype following Atypical Hemolytic Uremic Syndrome of Three Southeastern European Countries with a Literature Review

“…Even though the MCPggaac haplotype might not have an additional effect on MCP expression in all cases, the MCPggaac haplotype acts as a strong risk variant of aHUS onset or serves as a compound heterozygosity added to other heterozygous mutations (case 7). MCPggaac polymorphism is associated with a reduced risk of relapse and late aHUS onset in the absence of trigger and/or additional aHUS mutations [27].…”

Membrane cofactor protein (MCP; CD46): deficiency states and pathogen connections

“…Additionally, a specific MCP SNP block in the promoter region, termed the MCPggaac risk haplotype, may be associated with decreased transcriptional activity. This has been linked to aHUS, but only if associated with a causative variant in another complement regulator or AP component ([ 43 , 44 ], and reviewed in Ref. [ 40 ]).…”