MedUni Vienna: Newly discovered rare disease helps understand the complexity of bowel homeostasis

A single-gene mutation may cause a severe bowel disease in children. This could be shown in a recent study by an international research team   led by Kaan Boztug at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) together with Michael Lenardo, National Institute of Health (NIH), Bethesda. The newly discovered alterations lead to total loss of a protein called CD55, causing life-threatening bowel inflammation, chronic diarrhea and vascular thrombosis. The researchers unraveled the underlying molecular mechanisms and discovered previously unknown regulatory pathways relevant to bowel homeostasis. As a consequence of their findings, the researchers could identify a clinically approved drug which may specifically interfere with aberrant signaling involved in this previously unknown disease. The manuscript has now been published in the renowned New England Journal of Medicine.

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 complex regulatory mechanisms of bowel homeostasis, which could eventually be relevant for other types of rare and common diseases.

Service: New England Journal of Medicine
„CD55 Deficiency, Early-Onset Protein-Losing Enteropathy and Thrombosis“
Ahmet Ozen*, William A. Comrie*, Rico Chandra Ardy*, Cecilia Domínguez Conde, Buket Dalgic, Ömer Faruk Beser, Aaron R. Morawski, Elif Karakoc-Aydiner, Engin Tutar, Safa Baris, Figen Özcay, Nina Kathrin Serwas, Yu Zhang, Helen F. Matthews, Stefania Pittaluga, Les R. Folio, Aysel Unlusoy Aksu, Joshua J. McElwee, Ana Krolo, Ayca Kiykim,  Zeren Baris, Meltem Gulsan, Ismail Ogulur, Scott B. Snapper, Roderick HJ Houwen, Helen L. Leavis, Deniz Ertem, Renate Kain, Sinan Sari, Tülay Erkan, Helen C. Su, Kaan Boztug# and Michael J. Lenardo# (* and #: equal contribution); published in New England Journal of Medicine on 28 June 2017. DOI: 10.1056/NEJMoa1615887

The presented study was supported by the European Research Council (ERC Starting Grant to Kaan Boztug), the Austrian Academy of Sciences (ÖAW DOC fellowship 24486 to Rico Ardy), the National Institutes of Health (NIH), the Turkish National Grant Agency TUBITAK, and the American Diabetes Association and the National Institute of General Medical Sciences (NIGMS).

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