Relevance to Autism

Recurrent mutations in the POGZ gene have been identified in multiple individuals with ASD as described below. De novo variants in the POGZ gene were initially identified in autistic probands in two separate reports. In the first, 1 of 175 de novo frameshift variants was found in the POGZ gene in Neale et al., 2012 (PMID 22495311). In the other, 1 of 343 likely gene-disrupting variants was found in the POGZ gene in Iossifov et al., 2012 (PMID 22542183). No likely gene-disruptive variants in POGZ were observed in controls (although many missense variants have been observed in EVS). A third de novo LoF variant in the POGZ gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014 (PMID 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified POGZ as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo LoF variants in POGZ were identified in White et al., 2016 in individuals with developmental delay/intellectual disability and, in two cases, ASD (PMID 26739615). Furthermore, a review of clinical information in individuals with POGZ variants in this report identified shared phentoypic features (developmental delay/intellectual disability, hypotonia, behavioral abnormalities, similar facial features) and proposed that POGZ LoF variants were responsible for a form of syndromic intellectual disability. Additional LoF variants in POGZ were identified in previously unreported cases with developmental delay/intellectual disability and/or ASD in Stessman et al., 2016 (PMID 26942287). The authors of this report estimated that protein-truncating POGZ variants were significantly enriched in individuals with ASD and/or intellectual disability in comparison to the general population (p=4.19E-13, odds ratio 35.8), and that the penetrance of POGZ LoF variant was 65.9% given the incidence of ID (5.12%) in the general population. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified POGZ as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

The protein encoded by this gene appears to be a zinc finger protein containing a transposase domain at the C-terminus. This protein was found to interact with the transcription factor SP1 in a yeast two-hybrid system. Plays a role in mitotic cell cycle progression and is involved in kinetochore assembly and mitotic sister chromatid cohesion. Probably through its association with CBX5 plays a role in mitotic chromosome segregation by regulating aurora kinase B/AURKB activation and AURKB and CBX5 dissociation from chromosome arms.

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Model Summary

Mice with Pogz KD show impaired cortical neuronal development, impaired neuronal migration and differentiation, increased neuronal excitability, and impaired mature cortical network function. Het POGZ^WT/Q1038R mice bearing the Q1038R mutation identified as de novo mutations in ASD patients, show reduced body weight, and brain size in adulthood, normal survival, decreased cortical thickness, no gross morphological changes, altered gene expression in NSCs, decreased anxiety, decreased sociability, increased self grooming, decreased juvenile play, increased usv frequency and duration, and increased activity of excitatory cortical neurons. POGZ^Q1038R/Q1038R mouse embryos (E15.5) showed a ventricular septal defect, which likely results in embryonic lethality. Compensatory inhibition of increased neuronal excitability in POGZ mutants using anti-epileptic agent perampanel restores sociability in het POGZ^WT/Q1038R mice.

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