Study: Two cases of aHUS linked to CFH-CFHR1 hybrid genes
Genetic variations not seen in healthy people, suggesting connection
CFH-CFHR1 hybrid genes resulting from an abnormal combination of two genes were identified in a pair of Japanese patients with atypical hemolytic uremic syndrome (aHUS).
The genetic variations weren’t observed in healthy people, suggesting aHUS might be related to the hybrid genes being present.
“Our study emphasizes that the combination of functional and genetic analyses can more accurately elucidate the genetic origin and, ultimately, the biomolecular mechanisms of aHUS,” the researchers wrote in the study, “CFH-CFHR1 hybrid genes in two cases of atypical hemolytic uremic syndrome,” which was published in the Journal of Human Genetics.
aHUS is caused by the abnormal activity of part of the immune system, known as the complement cascade, leading to inflammation and blood clotting in small blood vessels, particularly in the kidneys.
Most people with aHUS have inherited mutations in genes that regulate the function of the complement cascade, including the CFH/CFHR gene cluster. Genetic mutations are thought to predispose people to the disease, but mutations alone aren’t usually enough to cause it. In most cases, a triggering event, such as an infection, is necessary.
The CFH protein is composed of 20 small conserved repetitive (SCR) domains known as complement control protein modules. These modules bind to proteins of the complement system to regulate their function.
The CFH/CFHR cluster, which includes six genes (CFH, and CFHR1 to CFHR5) are near each other on chromosome 1 and share a similar genetic sequence. Considering their proximity and similarity, large portions of DNA may be deleted, duplicated, or rearranged within the cluster, leading to so-called hybrid genes, which are formed by the combination of two separate genes.
Hybrid genes and aHUS
Researchers in Japan reported two cases of aHUS in patients with CFH/CFHR1 hybrid genes carrying new points of DNA rearrangement.
A 36-year-old woman and a 55-year-old man were found to have a genetic abnormality in plasma, as deduced from a functional assay to detect complement impairment mainly associated with CFH. The assay evaluates the level of red blood cell destruction, a common disease symptom.
In both patients, screening in aHUS-related genes, including CFH, didn’t reveal any disease-related mutations and no antibodies against CFH were detected. Two unusual copy number variations were detected in the CFH-CFHR gene cluster, however.
In the woman and in three of her family members, there was a heterozygous deletion of part of the CFH gene and a duplication of part of the CHFR1 gene, leading to the production of a protein expected to lack the end portion of CFH (SCRs 19 and 20) and include two SCR domains from the CFHR1 protein. Heterozygous means the rearrangement only occurred in one chromosome from one parent and that genes in the other chromosome were normal.
The man had a heterozygous deletion from part of the CFH gene to the CHFR1 gene. This led to the formation of a hybrid gene that likely contained instructions for making a protein lacking the last SCR region of CFH, which was fused to the last SCR domain of CFHR1.
“This is the first time that hybrid genes are reported as a cause of aHUS in Japanese cases,” the researchers wrote.
Looking into the copy numbers of the CFH/CFHR1 gene cluster in 2,036 people from the general population, the researchers found the copy numbers of the CFH gene were all normal, unlike aHUS-related hybrid genes.
Six types of hybrid genes have been reported in the CFH/CFHR gene cluster to date. Four of these led to the production of proteins lacking the terminal part of CFH that was fused with the terminal part of the CFHR protein — similar to the two cases in this study. Hybrid proteins devoid of these CFH SCRs probably trigger the complement system to be overactive, the researchers said.
“In summary, we detected novel breakpoints that cause CFH-CFHR1 hybrid genes in two aHUS cases through [gene copy number variations] and functional analyses, and also confirmed the absence of [gene copy number variations] of the CFH gene in the general population,” the researchers wrote, noting patients suspected of having aHUS should “perform an integrated analysis based on a clinical examination, functional analysis, and detailed genetic investigation.”