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Updated: 06/27/2021 11:32 PM IS
Washington [US]June 27 (ANI): A rare genetic defect affecting what is known as the ALG2 gene can cause serious metabolic diseases in humans, experts said. This happens through the malformation of proteins and sugar molecules. To date, it has been difficult to study this congenital glycosylation disorder due to its rarity and complexity.
A research team led by Prof. Dr. Joachim Wittbrodt and Dr. Thomas Thumberger from the Center for Organizmal Studies (COS) at the University of Heidelberg finally succeeded in introducing the underlying mutation in the ALG2 gene into a fish model and thus investigating the causes of these complex diseases on a molecular level. The study was published in the journal Development.
Human cells are kept alive by the activity of millions of proteins. As they ripen, these proteins have to be modified in a variety of ways, for example by adding sugar molecules – a crucial change for proper function. Errors in this sugar addition process, also known as sugar decoration, are often fatal at a very early stage of development.
As Prof. Wittbrodt explains, in rare cases a genetic defect leads to a lack of sugar addition, which then manifests itself as a congenital glycosylation disorder. “Correct protein glycosylation requires a series of enzymes that work like clockwork,” says the researcher.
The ALG2 gene has a particularly important role in this. It codes for an enzyme that is required for the correct branching of the sugar chain. If this process is disturbed, patients appear unaffected at birth, but develop problems in various organs such as the eyes, brain, and muscles in early childhood.
The team around Prof. Wittbrodt and Dr. Thumberger used the CRISPR / Cas9 gene editing scissors to introduce an ALG2 mutation into a fish model, the Japanese rice fish, or medaka. “Fish are particularly good models for these diseases because they develop outside the mother and are therefore very suitable for examining early embryonic defects,” explains Dr. Thumberger.
In addition, the genome of the Japanese rice fish can be processed efficiently and precisely. “Our fish are, so to speak, genetic twins, so that the effect of individual changes in comparison to non-genetically modified fish is directly recognizable.”
Although the evolutionary distance between humans and fish is great, the researchers report many of the same symptoms in the fish model that occur in ALG2 patients, including specific neuronal defects. They were surprised by the results of the analysis of the entire Medaka organism, which took into account the entire spectrum of different cell types.
“Although all cells of the fish showed the same reduced ALG2 activity, some cell types were more affected than others,” says Prof. Wittbrodt. In the fisheye’s retina, the cone cells required for color perception were unaffected, but there was a progressive loss of the rod cells required for vision in low light, making the fish night-blind. The researchers now hope to identify the proteins that cause the rod cells to die off due to reduced sugar binding.
Building on this, the Heidelberg research team wants to investigate the molecular mechanisms and causes for the development of such complex metabolic diseases in humans. (ANI)
