Serendipitous Finding Leads to Promising Mouse Model for Severe Genetic Disorder Known As NGY1 Deficiency

Researchers from the RIKEN Global Research Cluster in Japan have developed a potential mouse model for the genetic disorder known as an NGLY1 deficiency. Published online on April 20, 2017 in the journal PLOS Genetics, the study describes how a complete knockout of the Ngly1 gene in mice leads to death just before birth, which can be partially rescued by a second knockout of another gene called Engase. When related genes in the mice used for making the knockouts are variable, the doubled-deletion mice survive and have symptoms that are analogous to humans with NGLY1-deficiency, indicating that these mice could be useful for testing potential therapies. NGLY1-deficiency is a relatively newly discovered genetic disorder, with the first patient identified in 2012. The symptoms are severe, and include delayed development, disordered movement, low muscle tone and strength, and the inability to produce tears. Understanding how lack of NGLY1 leads to these symptoms is critical when considering targets for therapeutic interventions, and creating useful animal models of the disease is therefore equally important. The RIKEN team has already had some success studying the consequences of Ngly1 deficiency in cultured animal cells. The Ngly1 gene codes for an enzyme that helps remove sugar chains from proteins that are scheduled for degradation. Their research showed that when Ngly1 was absent, sugars normally removed by Ngly1 were improperly removed by another enzyme called ENGase. Knocking out the ENGase gene led to normal protein degradation. The open-access PLOS Genetis article is titled “Lethality of Mice Bearing a Knockout of the Ngly1-Gene Is Partially Rescued by the Additional Deletion of the Engase Gene.”
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