A Giant Leap Towards Rare Genetic Diseases

A genetic disease is caused by an abnormal genome. The abnormality can range from a single mutation to a gross chromosomal abnormality. Some genetic disorders are inherited, while others are caused by acquired mutations in pre-existing genes. There are approximately 7,000 different types of diseases and disorders. It is estimated that 350 million people worldwide suffer from unusual genetic diseases. Rare genetic diseases, and their symptoms, are uncommon and thus represent a large medical challenge and serious public health problem.

It is already known that NGLY1 deficiency, associated with an extremely rare genetic disease, is the cause of a congenital disorder of glycosylation variant. People with NGLY1 mutation have many severe symptoms, from delayed development and epilepsy to abnormal liver function and the inability to make tears.

To have a more clear picture of the effects of this mutation, researchers from the RIKEN-Max Planck Joint Research Centre, Japan showed the enzyme ENGase as a factor responsible for deficient protein degradation arising from the absence of mouse Ngly1 gene expression. The study described how lack of Ngly1 peptide resulted in partial removal of sugar residues, resulting in abnormal glycoprotein aggregation in cytostol.

The researchers first created a model glycoprotein and expressed it in cells derived from four types of mice: wild-type, Ngly1 knockout, Engase knockout, and double knockout. They estimated the extent of its degradation and the amount of sugar attached to un-degraded protein. They found that only double knockout cells contained sugar chains attached with the model protein. However Ngly1 knockout cells contained a normal proportion of de-sugared model protein, indicating that ENGase might be responsible for the deglycosylation. Moreover inhibition of protein synthesis led to normal protein degradation in all the cell types. However the amount of de-sugared protein remained high and undegraded in the Ngly1 knockout cells.

Based on the findings the scientists concluded:

  • Removal of sugar chains by ENGase produced a specific type of protein that, in the absence of Ngly1 could not be degraded properly due to incomplete removal of sugar molecules, confirmed by mass spectrometry.
  • Normal protein degradation in the double knockout indicates that deglycosylation of the model protein by Ngly1 was not necessary as long as the incomplete removal of sugars by ENGase was prevented.

The association between the physiological symptoms, observed in NGLY1 deficiency, and reduced protein degradation is still not established. However, the scientists speculate that inhibition of ENGase activity may serve as a therapeutic target for patients carrying mutations in the NGLY1 gene.

Journal Reference:

Endo-β-N-acetylglucosaminidase forms N-GlcNAc protein aggregates during ERAD in Ngly1-defective cells. Chengcheng Huang, Yoichiro Harada, Akira Hosomi, Yuki Masahara-Negishi, Junichi Seino, Haruhiko Fujihira, Yoko Funakoshi, Takehiro Suzuki, Naoshi Dohmae, and Tadashi Suzuki.  Proc. Natl. Acad. Sci., January 2015 DOI: 10.1073/pnas.1414593112

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Arunima Maiti

Arunima Maiti

Biomedical scientist with special interest in reproductive biology.

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