Study links gene mutation with metabolic diseases in humans

A rare genetic mutation is responsible for serious metabolic diseases in humans. New findings from the Centre for Organismal Studies (COS) of Heidelberg University can allow researchers to take a closer look at the underlying causes of health issues related to metabolism by studying them at a molecular level.

The rare genetic defect to the ALG2 causes the defective formation of proteins and sugar molecules which leads to a congenital glycosylation disorder. The defect causes a malfunction in the sugar-adding process known as sugar decoration.

Correct protein glycosylation requires a number of enzymes functioning together like clockwork. Researchers found that the ALG2 gene plays a crucial role by coding an enzyme needed for the correct branching of the sugar chain, reported The Wire. People who have the genetic defect in ALG2 will start experiencing sugar addition deficiencies which will eventually manifest as congenital disorders of glycosylation.

Cells in the human body rely on the activity of proteins which undergo many modifications as they mature. Some of these modifications happen through the addition of sugar molecules. This is crucial to the proper functioning of proteins and cells.

The team led by Prof. Wittbrodt and Dr Thumberger used Japanese rice fish (medaka) to study the disorder. ALG2 mutation was introduced using the CRISPR/Cas9 gene-editing scissors. Dr Thumberger said that fish are good models to study such early embryonic defects because they develop outside the mothers, said The Wire report.

The genome of the Japanese rice fish can also be edited efficiently and precisely. The team used genetic twins to observe individual changes.

The findings suggest that any disturbance in the sugar decoration process will lead to eventual problems in the eyes, brain, and muscles. The individual may appear unaffected at birth, but the organs will start experiencing symptoms in early childhood.

Experts think that similar symptoms seen in the fish models will show up in ALG2 patients as well even though the two species are vastly different.

The team is keen to see the results as some types of cells were affected more in the fish model. Prof. Wittbrodt said that the cone cells in the retina which are responsible for colour-sensing were unaffected. However, the rod cells responsible for vision in low light or night vision experienced a progressive loss. Scientists are trying to identify which proteins caused the rod cells to die.