Professor Masaaki Komatsu and visiting researcher Ryosuke Ishimura of the Graduate School of Medical and Dental Sciences, Niigata University have found that the gene encoding the protein-modifying activator "UBA5" is a severe developmental disorder associated with epilepsy and small head disease, which has been considered to be of unknown cause. The research result that it is due to the mutation was announced.It was elucidated in a joint research with the University of Helsinki and Niigata University, and the results of this research were published in "The American Journal Human Genetics".
In higher organisms, proteins synthesized based on gene sequences rarely exert their functions directly, and in many cases, various modifications such as phosphorylation, glycosylation, and methylation exhibit a variety of functions. NS.For example, "UBA5" is an enzyme that activates the ubiquitin-like protein UFM1. It is thought that UFM1 is activated and then transferred to the UFC1 enzyme, and finally modifies the intracellular target protein and is responsible for the functional conversion of the protein.
The research group identified five European families with severe developmental disabilities with epilepsy and microcephaly and performed genetic analysis, and found that the gene encoding UBA5 was mutated.UBA5 protein with patient-derived mutations had reduced enzymatic activity, resulting in inhibition of protein modification by UFM5.Furthermore, when mice specifically deficient in the UFM1 gene were created and analyzed, the results showed that microcephaly accompanied by nerve cell death developed and died within a few days after birth.These results suggest that abnormalities in the UFM1 protein modification mechanism cause hereditary severe developmental disorders.
The proportion of UBA5 gene mutations identified this time is said to be 0.28% among Europeans, and it is considered that there are many patients with severe developmental disabilities who have UBA5 mutations.Recently, a gene mutation in UBA5 was also reported from a family in China with a patient with pediatric cerebellar degenerative disease.In the future, we are aiming for clinical application by searching for Japanese patients with UBA5 gene mutations and at the same time screening for drugs that enhance UBA5 enzyme activity.
