The cause of the disease is a disorder in the formation of diphthamide, a protein modification of an enzyme (eEF2), which is required for the production of proteins in human cells. "In a way, diphthamide functions as a quality check in protein production," explains Koray Ütkür, PhD student in the Department of Microbiology and first author of a recently published study. If it is missing or too little of it is present, defective proteins accumulate in cells, affecting a range of important cell processes. In addition to mental disabilities, the deficiency also manifests itself in growth disorders in the womb, hand and foot anomalies and other symptoms.

In recent years, several gene variants that can cause the disease have already been identified, including by the Kassel Research Group and Roche. The current study built on this and investigated the DPH1 and DPH2 genes, which play a key role in inhibited diphthamide production. The gene variants (so-called alleles) produce different mutated DPH1/DPH2 enzymes. The research team has now identified 12 variants of DPH1 and DPH2 that impair diphthamide production and thus lead to the deficiency syndrome.

Ütkür worked with yeast cells as a model, which he specifically manipulated to induce the desired defects in DPH1 and DPH2. In the subsequent analysis, he found that ten specific alleles of the DPH1 gene and two variants of the DPH2 gene lead to diphthamide deficiency. "Yeast cells share these specific genes with us humans, so they are very well suited as a study model," he explains. The Roche Research Group confirmed his findings with studies on human breast cancer cells.

However, the deficit is only relevant to the disease if the corresponding mutations occur on both sets of chromosomes. The disease is therefore very rare, the frequency is probably far below one case per 50,000 people.

The Department of Microbiology, headed by Prof. Dr. Raffael Schaffrath, has been researching protein production in cells for a long time, including in a diphthamide pilot project supported by the Central Research Fund of the University of Kassel. Schaffrath is also supervising Ütkür's doctoral thesis. The fact that further causes of diphthamide deficiency syndrome have now been identified(whether and how many more there are is still unknown) does not automatically lead to the development of cures, at least for the foreseeable future. However, the cause of affected children can be diagnosed quickly in the future in order to better manage the disease.

Study in the journal "Disease Models and Mechanisms ": https://journals.biologists.com/dmm/article/16/9/dmm050207/329422