Researchers model complex metabolic disturbances – ScienceDaily

A rare genetic defect that affects the so-called ALG2 gene can cause serious metabolic diseases in humans. It does this by the faulty formation of proteins and sugar molecules. Until now, its rarity and complexity made it difficult to study this congenital glycosylation disorder. A research team led by Prof. Joachim Wittbrodt and Dr Thomas Thumberger of the Center for Organismal Studies (COS) at Heidelberg University finally succeeded in introducing the underlying mutation of the ALG2 gene into a fish model, thus allowing the causes of these complex diseases to be studied at the molecular level.

Human cells are kept alive by the activity of millions of proteins. As they mature, these proteins must be altered in a number of ways, for example by adding sugar molecules – a crucial change for proper functioning. The flaws in this process of adding sugar, also known as sugar decoration, are often fatal in the very early stages of development. As Professor Wittbrodt explains, in rare cases a genetic defect causes deficits in added sugar, which then manifest as congenital glycosylation disorders. “Correct glycosylation of proteins requires a number of enzymes working together like clockwork,” says the researcher. The ALG2 gene has a particularly important task in this process. It encodes an enzyme necessary for the proper branching of the sugar chain. If this process is disturbed, patients do not appear to be affected at birth but develop problems in different organs, such as the eyes, brain, and muscles, during infancy.

The team led by Professor Wittbrodt and Dr Thumberger used the CRISPR / Cas9 gene editing scissors to introduce an ALG2 mutation into a model of fish, Japanese rice fish or medaka. “Fish are particularly good models for these disorders because they develop outside the mother, which makes them very suitable for studying early embryonic defects,” says Dr Thumberger. In addition, the Japanese rice fish genome can be edited efficiently and accurately. “Our fish are genetic twins, so to speak, so the effect of individual changes can be directly identified compared to non-genetically modified fish.”

Although the evolutionary distance between humans and fish is vast, researchers are reporting many of the same symptoms in the fish model that appear in ALG2 patients, including specific neural defects. They were surprised by the results obtained by the analysis of the total medaka organism, which took into account the full spectrum of different cell types. “Although all cells in the fish showed the same reduced ALG2 activity, some cell types were more affected than others,” says Professor Wittbrodt. In the retina of the fish eye, the cone cells needed for color detection were not affected, but there was a gradual loss of the rod cells needed for low-light vision, thus making the fish blind at night. . Researchers now hope to identify the proteins that cause stick death due to decreased sugar binding.

“Our studies on the medaka fish model showed that all symptoms could be avoided by providing a fully functional ALG2 mRNA – the model for producing the correct ALG2 enzyme. We were able to effectively reverse the genetic defect in the fish model. . This means that we can now systematically analyze the individual functional domains of the ALG2 enzyme. We are particularly interested in the cell type-specific response in the context of the whole organism “, emphasizes Joachim Wittbrodt. Based on this research , the Heidelberg research team plans to study the molecular mechanisms and causes of the development of these complex metabolic diseases in humans.

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Materials provided by University of Heidelberg. Note: Content can be changed for style and length.

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