Recently, Chinese scientists, supported by the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province and other programs, have revealed the pathogenesis of human ANCHORIN REPEAT DOMAIN 2 (SHANK2) gene mutation in autism. Relevant achievements were published in Molecular Psychiatry.
In recent years, large-scale genetic research on the cohort of patients with autism spectrum disorders has revealed a number of risk genetic loci and candidate gene variations related to autism spectrum disorders. Further use of targeted differentiation technology of pluripotent stem cells induced by adult cell reprogramming of patients can deeply analyze the targeted effect mechanism of population specific genetic variation, and to some extent overcome the limitations of transformation application caused by genetic background bias in cross species research. However, based on the humanized neural cell model, the research on the genetic mechanism of specific neuronal subtypes is relatively lacking.
Shi Lingling, associate researcher of the Guangdong Hong Kong Macao Central Nerve Regeneration Institute of Jinan University, and the team of researchers Zhang Zhang, as well as Chen Jiekai, a researcher of the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, have not previously reported the mutation of SHANK2Y29X gene based on the cohort study of patients with autism spectrum disorders, Bioinformatics predicts that this mutation will lead to the early generation of a stop codon in the translation process of the SHANK2B transcript of the SHANK2 gene, which hinders the normal synthesis of the SHANK2 protein.
Based on the pedigree analysis of the autism spectrum disorder patient, the patient's iPSC derived multi subclass neuron differentiation culture model and the construction of the SHANK2BY29X KI gene knockout mouse model, the research team innovatively found that: first, SHANK2BY29X had a differential impact on different transcripts of SHANK2, and further selectively damaged the early development of ALDH1A1 negative dopamine neurons; Second, we verified the potential role of SHANK2BY29X genetic variation in the social disorder related to autism spectrum disorder through iPSC cell induced differentiation model from patients and transgenic mouse model.
Through precise molecular regulation and cell research techniques, this study makes up for the lack of in-depth understanding of the functional specificity of SHANK2 in previous studies, and provides a possible molecular target for future intervention strategies against specific neurodevelopmental disorders.
Relevant paper information: https://doi.org/10.1038/s41380-024-02578-6
