Among the plethora of genetic alterations, those causing a complete block of protein production belong to the most severe mutations. When a stopping signal, a so-called stop codon is inserted into a protein’s genetic blueprint, the resulting protein products are dysfunctional. Considered useless, they are usually guided to a cell’s degradation machinery – a process that potentially causes disastrous consequences for an organism.
In a young female patient suffering from early-onset inflammatory bowel disease and protein-losing enteropathy, such a severe type of mutation was identified by the team of Kaan Boztug, director of the newly founded LBI-RUD and affiliated principal investigator at CeMM and the Medical University of Vienna. The resulting study was recently published in the New England Journal of Medicine.
The little girl who had undergone numerous hospitalizations and therapeutic attempts suffered from various symptoms from early childhood, ranging from severe diarrhea to recurrent infections, chronic malnutrition and concomitant failure to thrive. With a genetic investigation, a so-called exome sequencing, which identifies and reads all protein-encoding genes, Kaan Boztug´s group could shed light on the clinical mystery: Rico Ardy, a PhD candidate in Boztug’s team, could identify a stop codon within the gene sequence of the protein CD55, which is a key regulator of the innate immune system. Yet a definite proof of whether this single mutation was causal for the complex disease manifestation of this unique patient needed even more detailed molecular investigations.
At this stage, Kaan Boztug’s involvement in international networks of researchers working on rare diseases proved beneficial: Michael Lenardo, long-standing collaborator at the US-based National Institutes of Health (NIH), had independently identified two other families with index patients exhibiting similar clinical symptoms who also carried inherited mutations in the CD55 gene. Subsequently, the research team which was jointly led by Kaan Boztug and Michael Lenardo was able to identify a total of 11 patients, and addressed the detailed molecular mechanisms: Absence of CD55 protein dampened a proper control of the complement system, an important component of innate immune defense, inducing proinflammatory cytokine signaling. Concomitantly, the researchers could show that loss of CD55 led to impaired production of IL-10, a key anti-inflammatory signaling molecule in the gut.
The combination of these effects lead to a severe clinical disease which may be life-threating: The over-functioning complement system collapses in the absence of regulatory IL-10 molecules. The observed bowel inflammation is an immediate consequence, enforced by the constant immune cell stimulation through the gut flora, where fine-tuned regulatory mechanisms are of particular relevance. Inflamed intestinal lymphatic vessels lead to loss of protein through blood plasma, a major disease manifestion of CD55 deficiency, accompanied by a risk of thrombosis.
After deciphering the molecular consequences of this particular genetic defect, the investigators aimed at identifying a potential targeted therapy for this condition, and were successful: A clinically approved drug that dampens complement activity could also be applied in case of absent CD55 protein.
“This disease is an ideal example for the importance of rare disease research,” says Kaan Boztug. “By investigating the molecular mechanisms underlying the disease, we are then able to strategically test for re-purposing approved medications for a personalized therapy. Furthermore, through investigating single genetic defects, we are able to unravel novel aspects of the biological function of the affected gene.”
The role of CD55 in maintaining bowel homeostasis was hitherto largely unexplored. Similarly, the molecular mechanisms underlying protein loss in the bowel – a process that plays a role in a wide array of diseases – were widely unknown. Here, the present study provided important insights that widen our understanding of the comp