NYMU, CGMH and the Cross-Country Collaboration Research Team Discovered a New Gene associated with “Lissencephaly”

22 9 月, 2020

National Yang-Ming University Institute of Brain Science Professor Tsai, Kaoshiung Chang Gung Memorial Hospital Department of Brain Function and Epilepsy Director Tsai and National Yang-Ming University Institute of Biochemistry and Molecular Biology Associate Professor Wang have cooperated with research teams across the country to utilize Next Generation Genetic Analysis. They have discovered that CEP85L is a new gene associated with lissencephaly. The team confirmed that loss of function of CEP85L leads to a defect in neural cell migration and this defect is related to the functioning of centrosome. This is the first centrosome composition gene found to be involved in lissencephaly. The research was published in April 2020 in the important journal “Neuron“.

“Lissencephaly” is a serious brain developmental abnormality and patients show serious developmental delay, as well as intractable epilepsy. The most serious patients usually lack language, are unable to swallow and cannot walk; these patients become a huge burden on their families. Lissencephaly is a relatively rare disease and has an incidence of about 12 individuals per million. In Taiwan, there are around 300 cases.

A normal brain has many folds called gyri, and these are direct involved in high-order cognitive function development. Patients with lissencephaly have gyri that are underdeveloped or not developed at all; thus their brains have a smooth appearance that is called lissencephaly. The corresponding author of the paper, Professor Tsai, remarked that part of the lissencephaly phenotype of patients is caused by a genetic mutation. During the development of the brain, neural cells move to the surface of the brain (the cortex) and this process is regulated by many genes. If any of these genes are defective, the neural cells are unable to move to their correct location and this can lead to abnormal development of gyri or lissencephaly.

Kaoshiung Chang Gung Memorial Hospital Department of Brain Function and Epilepsy Director Tsai and Linkou Chang Gung Department of Dermatology Director Chung cooperated from the beginning of this research. Using Next Generation Genetic Analysis, they found CEP85L genes present in patients with lissencephaly and epilepsy are mutated. Up to this point, CEP85L had never been associated with any human diseases and thus the identification of mutants of CEP85L and its association with lissencephaly is a world first.

Later, Dr. Tsai cooperated with National Yang-Ming University Institute of Brain Science Professor Tsai. The NYMU team is responsible for the animal and cell experiments in this study. These animal and cell models were able to confirm that the gene truly also affects brain development, specifically in mice. The protein from the gene was found to be located on the centrosome and thus this gene is the first gene related to centrosome composition and activity to be shown to be involved in lissencephaly. Later, using international cooperation with Australia, USA, and Malaysia, the team was able to identify another twelve patients around the world who also have CEP85L gene mutations. These findings further confirmed the role of CEP85L in brain development.

This important discovery should help to accelerate the diagnosis of this type of abnormal brain developmental disease by doctors and it also helps to explain why some newborns are found to have this serious disease without any family history. This gene could be used for prenatal screening in the future, which should decrease the occurrence of this disease. In terms of the science, this research has provided scientists with a deeper understanding of the mechanisms behind brain development and may also help to guide drug development and/or genetic therapy in the future.