Abstract
Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.
Highlights
Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; the neurobiological basis behind these disorders remains unknown
We performed cellular fractionation experiments using human SH-SY5Y cells and the human Q1042R-mutated POGZ and obtained essentially the same results as the results with the mouse Q1038R mutation in Fig. 1g, h (Supplementary Fig. 3). These results suggest that ASD-related de novo mutations but not control de novo mutations identified in unaffected controls impair the nuclear localization of POGZ in cells
Recent genetic and epidemiological studies suggest that the compromising of POGZ function by de novo mutations is likely to be involved in ASD; the contribution of de novo POGZ mutations to ASD onset remains largely unclear
Summary
Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; the neurobiological basis behind these disorders remains unknown. A recent, comprehensive exome analysis has identified 65 high-confidence ASD genes[20] Among these high-confidence ASD genes, recent studies have found that haploinsufficiency of ARID1B or CHD8 causes ASD-related abnormalities in mice[21,22,23,24,25,26,27], further direct assessments of the biological significance of ASD-associated de novo mutations are necessary to fully understand the contribution of de novo mutations to the core features of ASD. WRT1001HF1047HL1080R transcription factor, heterochromatin protein 1 (HP1), and chromodomain helicase DNA-binding protein 4 (CHD4)[35,36,37], which suggests that POGZ functions as a chromatin regulator; the role of POGZ in brain development and the biological significance of ASD-associated de novo POGZ mutations in the etiology of ASD are largely unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
