Mar 10, 2020

Principal investigators, Takanobu Nakazawa (A01) and Kaoru Seiriki (A03) published the Nature Communications paper reporting that ASD-associated de novo mutations on the POGZ gene impair cortical development and reversible autism-like phenotypes in mice.

Autism spectrum disorders (ASD) are characterized by early life onset with aberrant brain development, leading to social and cognitive abnormalities. Despite the high heritability of ASD, recent studies have suggested that the disease is highly genetically heterogeneous and that the genetic cause is unidentified in approximately 70~90% of patients; the molecular etiology of ASD remains obscure. Accordingly, there are no pharmacological medications to treat the core symptoms of ASD. Recent genetic studies have suggested that de novo mutations, spontaneous rare mutations that appear in an affected child but not the unaffected parents, significantly contribute to ASD. However, the biological phenotypes of each ASD-associated de novo mutation have been unexplored.

In this study, Nakazawa and Seiriki developed the first mouse model that carried a pathogenic de novo mutation of POGZ identified in an ASD patient. They also established induced pluripotent stem cell lines with the same de novo POGZ mutated (Q1042R) as the model mouse. Comprehensively examining these materials, they found that the de novo mutation in POGZ caused impaired cortical neuronal development and reversible autism-like behavioral abnormalities. Together, these observations provide the first in vivo evidence suggesting that ASD-associated de novo mutations in a high-confidence ASD gene cause a wide range of aspects of the ASD phenotypes.

Figure Legend:
Impaired differentiation of patient-iPSC-derived neural stem cells into neurons. 

Press Release

Nature Communications