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.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Patterns and rates of exonic de novo mutations in autism spectrum disorders.
Broadening the clinical spectrum of White-Sutton syndrome, implications for co-morbidity with celiac disease in a patient with a novel likely pathogenic variant in the POGZ gene
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
A novel patient with White-Sutton syndrome refines the mutational and clinical repertoire of the POGZ-related phenotype and suggests further observations
Unveiling Hidden Genetic Architectures: Molecular Diagnostic Yield of Whole Exome Sequencing in 50 Children With Autism Spectrum Disorder Negative for Copy Number Variations
51 pediatric cases diagnosed with non-syndromic ASD (according to DSM-V criteria) and a control group consisting of 50 children of similar age group without neurodevelopmental problems.
51 pediatric cases diagnosed with non-syndromic ASD (according to DSM-V criteria) and a control group consisting of 50 children of similar age group without neurodevelopmental problems.
51 pediatric cases diagnosed with non-syndromic ASD (according to DSM-V criteria) and a control group consisting of 50 children of similar age group without neurodevelopmental problems.
51 pediatric cases diagnosed with non-syndromic ASD (according to DSM-V criteria) and a control group consisting of 50 children of similar age group without neurodevelopmental problems.
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.
References
Type
Title
Author, Year
Additional
POGZ Is Required for Silencing Mouse Embryonic β-like Hemoglobin and Human Fetal Hemoglobin Expression
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Exons 13-19, which encode the CENPB and DDE domains and a portion of the zinc finger region of the Pogz protein, were flanked by a loxP site at the 5â?² end and a FRT-NeoFRT-loxP cassette on the 3â?² end. To delete the neo cassette from the line, Pogz neo/neo mice were crossed with B-actin-flp mice to produce Pogz f/+ mice. These were subsequently crossed to B-actin-cre mice to produce heterozygous Pogz mice which were crossed to obtain homozygotes.
Allele Type: knockout
Strain of Origin: Genetic Background: C57BL/6
ES Cell Line: CJ7
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Wildtype
Mutation:
Four distinct commercial shRNAs, a miR30-based shRNA (shRNAmiR30) targeting Pogz and a pCAG-GFP reporter were injected into the lateral ventricle of E14.5 mouse forebrains to generate a Pogz KD mouse model. ASD related de novo mutant POGZ, R1004X,E1036K, Q1038R and E1043X were used as ASD-related positive controls and R1001H, F1047L, and H1080R were used as de novo mutant Pogz controls. Wt-Pogz construct was injected as control.
Allele Type: Knockdown
Strain of Origin: Genetic Background: ICR mice
ES Cell Line: Mutant ES Cell Line: Model Source: SLC, Shizuoka, Japan
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous POGZ^WT/Q1038R mice carrying the de novo ASD-related human Q1042R mutation were generated using CRISPR-Cas9 gene editing. Offsprings of Pogz heterozygous male and wildtype female matings were analyzed. BRC strain number RBRC09544.
Allele Type: Loss of function
Strain of Origin: Genetic Background: C57BL/6NJcl
ES Cell Line: Mutant ES Cell Line: Model Source: CLEA Japan, Tokyo, Japan
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homozygous POGZ^Q1038R/Q1038R mice carrying the de novo ASD-related human Q1042R mutation were generated using CRISPR-Cas9 gene editing. Offsprings of Pogz heterozygous male and wildtype female matings were analyzed. BRC strain number RBRC09544.
Allele Type: Loss of function
Strain of Origin: Genetic Background: C57BL/6NJcl
ES Cell Line: Mutant ES Cell Line: Model Source: CLEA Japan, Tokyo, Japan
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Crispr/cas9 and sgrnas targeting was used to ablate exons 1 and 6 (10kb) of pogz resulting in a premature stop codon.
Allele Type: Knockout
Strain of Origin: C57BL6/J
Genetic Background: C57BL6/J
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Rubenstein Lab
Description: Pogz null embryos rarely survived beyond embryonic day 16.5, embryos were absorbed as early as E10.5, but we observed a consistent drop in animal survival around E15.5
Description: Mutants show increased proportion of pax6+ nscs and decreased the proportion of tbr2+ ips and satb2+ young neurons without affecting migration in the somatosensory cortex, indicating pogz plays a role in promoting neuronal differentiation.
Exp Paradigm: Pax6, tbr2, satb2
Description: Mutants show decreased migration of gfp positive mutant cells in the developing somatosensory cortex. forced expression of wt mpogz restored normal migration. pogz knockdown mutants show decrease in the number of gfp positive cells in the upper cortical plate and an increase in gfp positive cells in the intermediate zone indicating a decrease in migration at e18.5. mutants show no significant migration defects in cortices at e16.5. asd-related pogz mutants failed to rescue neuronal migration. control pogz mutants rescued neuronal migration in pogz knockdown mutants to the same level as wt-mpogz expression. over-expression of asd related mutants show decreased number of gfp positive cells in the cortical plate and increase in the number of gfp positive cell
Exp Paradigm: NA
Description: Mutants show decrease in total cortical thickness, decrease in the thickness of layer ii-iv and increase in thickness of layer v at the somatosensory cortex.
Exp Paradigm: NA
Description: Mutants show abnormal distribution of cux1+ excitatory neurons with decrease in the number of excitatory pyramidal neurons in the upper cortical layer, but no change in distribution of gaba+ inhibitory neurons.
Exp Paradigm: NA
Description: Mutants show decreased number of satb2+ brdu+ cells in the upper layer and an increased number of satb2+ brdu+ cells in the lower layer in the developing cortex.
Exp Paradigm: NA
Description: Mutants show decreased density of the satb2+ neurons (layer ii/iii) in the upper layer and increased in the lower layer in the developing somatosensory cortex.
Exp Paradigm: Satb2
Miniature post synaptic current frequency: excitatory1
Increased
Description: Mutants show increase in frequency of miniature excitatory postsynaptic currents (mepscs) in pyramidal neurons in layer ii/iii of the acc.
Exp Paradigm: NA
Description: Juvenile mutants spent less time in active interactions, such as sniffing, allogrooming, chasing, and playing with a male non-sibling intruder.
Exp Paradigm: NA
Description: Mutant pups emitted more and longer usv calls with an altered call pattern including increased proportions of two-syllable and flat calls and decreased composite calls and frequency steps, indicating a disturbance in communication.
Exp Paradigm: NA
Description: Mutants show differential expression of genes in the embryonic cortex that are common in human and mice and enriched for go annotations involving cellular and organismal development, particularly neuronal development.
Exp Paradigm: NA
Description: Lack of hippocampal theta synchrony in local field potentials from the mpfc and vhpc at baseline and as mice approached and remained the center of the epm
Description: Decreased communication between mpfc and vhpc indicated by no differences in power of theta synchrony in the vhpc or mpfc and independent component analysis; deficit in the transmission of neural activity from the vhpc to mpfc
