SEU Prof. Han Junhai’s research team from the School of Life Science and Technology, along with the Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, has recently published their latest findings inNature Communications. The paper — titled“The missense mutation Y65C in PQBP1 causes microcephaly and cognitive deficits through a combination of partial loss-of-function and gain-of-function effects” — systematically explains the molecular mechanism behind the Y65C point mutation in the PQBP1 gene, which is associated with X-linked intellectual disability syndrome. The mutation results in microcephaly through both “l(fā)oss-of-function” and “gain-of-function” effects, offering new insights for the treatment of related diseases.

Renpenning syndrome is an X-linked genetic disorder, typically presenting with intellectual disabilities and microcephaly. This disease is mainly caused by mutations in the polyglutamine-binding protein 1 (PQBP1) gene. The Y65C missense mutation in this gene leads to the most severe clinical symptoms, though its pathogenic mechanism was previously unclear. The research team constructed a Pqbp1Y65C/Y-KI mouse model and revealed that this mutation affects brain development through dual pathways. On one hand, it causes a typical loss-of-function effect — the mutation leads to a decrease in PQBP1 protein levels, which in turn slows down the proliferation of neural progenitor cells. On the other hand, it also triggers a gain-of-function effect — the mutation enhances the binding of PQBP1 to the key regulatory factor Fip1l1, thereby disrupting the process of alternative polyadenylation (APA), affecting the maturation and stability of mRNA, and ultimately leading to abnormal neuronal differentiation. This study has not only clarified the pathogenic mechanism of the PQBP1-Y65C mutation in causing microcephaly but also provided a model for understanding the pathogenesis of genetic diseases, offering new strategies for potential treatments.

The paper’s co-first authors are PhD student Yuan Linjuan, Associate Professor Cheng Shanshan, and Postdoctoral Fellow Liu Xian, while Prof. Han Junhai and Prof. Zhang Zichao are the co-corresponding authors. This research was supported by the STI2030-Major Projects on “Brain Science and Brain-like Research” and the National Natural Science Foundation of China.

Paper’s link: https://www.nature.com/articles/s41467-025-68202-5

Source: School of Life Science and Technology, SEU

Translated by: Melody Zhang

Proofread by: Gao Min

Edited by: Li Xinchang