Alternative titles; symbols
HGNC Approved Gene Symbol: POGZ
SNOMEDCT: 772127009;
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38) : 1:151,402,724-151,459,494 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | White-Sutton syndrome | 616364 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated human brain cDNA library, Seki et al. (1997) cloned POGZ, which they designated KIAA0461. The deduced protein contains 1,355 amino acids.
Using the N-terminal activation domains of the transcription factor SP1 (189906) to screen a cDNA library originating from SW613-S human colon carcinoma cells, Gunther et al. (2000) cloned a splice variant of KIAA0461 that included an insertion of an additional 53 amino acids near the N terminus. The deduced 1,411-amino acid full-length protein has 9 putative zinc fingers of the C2H2 type and 2 proline-rich regions in a central domain, and small acidic stretches at both the N- and C-termini.
Nozawa et al. (2010) found that full-length 1,410-amino acid POGZ contains an irregular zinc finger motif following the central cluster of 9 C2H2-type zinc fingers and that the C-terminal domain contains a centromere protein B (CENPB; 117140)-like DNA-binding domain and a DDE domain that originated from a transposase encoded by a pogo-like DNA transposon.
By yeast 2-hybrid analysis, Gunther et al. (2000) found that the N-terminal half of KIAA0461 interacted with the N-terminal transactivation domains of SP1.
HP1-alpha (CBX5; 604478) has an essential role in heterochromatin formation and mitotic progression through interaction of its PxVxL motif with several cell cycle proteins. Nozawa et al. (2010) found that POGZ bound HP1-alpha, but via an atypical zinc finger, called the HP1-binding zinc finger-like (HPZ) domain, rather than the canonical PxVxL motif. POGZ bound HP1-alpha in a competitive manner with PxVxL motif-binding proteins such as TIF1-beta (TRIM28; 601742) and INCENP (604411). Knockdown of POGZ in human cell lines caused mitotic defects, with accelerated mitosis, abnormal chromosome segregation, nuclear fragmentation, and disrupted mitotic HP1-alpha localization and Aurora kinase B (AURKB; 604970) activity. The defects were similar to those caused by knockdown of Aurora kinase B. Expression of the HPZ domain alone corrected the mitotic defects in POGZ knockdown cells. Nozawa et al. (2010) concluded that the HP1-chromatin interaction is destabilized by binding of POGZ, permitting Aurora kinase B activation and mitotic progression.
Hartz (2012) mapped the POGZ gene to chromosome 1q21.3 based on an alignment of the POGZ sequence (GenBank AB007930) with the genomic sequence (GRCh37).
The Deciphering Developmental Disorders Study (2015) reported 2 girls with White-Sutton syndrome (WHSUS; 616364) who had heterozygous de novo mutations in the POGZ gene: one was a frameshift (614787.0001), and the other was predicted to result in loss of function (614787.0002). No functional studies were performed. Both girls had developmental delay and congenital anomalies.
In 25 unrelated patients with WHSUS, Stessman et al. (2016) identified de novo heterozygous truncating mutations in the POGZ gene (see, e.g., 614787.0007-614787.0010). Functional studies and studies of patient cells were not performed, but all of the mutations were predicted to disrupt the POGZ gene and result in a loss of function. Three additional patients with autism spectrum disorder were found to have de novo heterozygous missense variants in the POGZ gene; however, functional studies of the variants were not performed. The patients were ascertained from several large cohorts comprising over 17,000 patients with neurodevelopmental disorders who underwent whole-exome, whole-genome, or targeted sequencing. Stessman et al. (2016) estimated that POGZ mutations may be responsible for up to 0.14% of individuals with autism and/or intellectual disability.
In 5 unrelated children with WHSUS, White et al. (2016) identified 5 different heterozygous truncating mutations in the POGZ gene (see, e.g., 614787.0003-614787.0005). The mutations were shown to occur de novo in 4 patients; the mutation in the fifth patient was not present in the mother, but paternal DNA was not available. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were all predicted to result in truncated proteins lacking the DNA-binding domain, the DDE domain, and the coiled-coil domain. Functional studies were not performed, but all of the mutations were predicted to result in a loss of function. Two patients carried variants of unknown significance in additional genes (RAI1, 607642 and STIL, 181590, respectively), which may have contributed to the phenotype.
Assia Batzir et al. (2020) reported 22 individuals, including 2 who were previously reported by the Deciphering Developmental Disorders Study (2015), with 21 different heterozygous loss-of-function mutations in the POGZ gene, 15 of which were novel (see, e.g., 614787.0011); all patients had features consistent with White-Sutton syndrome. Eighteen mutations occurred de novo, 1 was inherited from a mildly affected mother, and parents were not tested in 2 other patients. Of the 21 mutations in this cohort, 19 were truncating (including a large deletion encompassing exons 4-19, 10 nonsense, and 8 insertion/deletions leading to frameshifts) and 2 were splice site mutations. Most of the mutations (57%) occurred within the last exon (exon 19), emphasizing the importance of this exon in POGZ function. Six of the truncating mutations were predicted to undergo nonsense-mediated RNA decay by computational analysis, whereas 13 were predicted to escape nonsense-mediated RNA decay. Review of a large clinical laboratory database showed that 13 out of 9,206 patients (0.14%) who underwent exome sequencing for neurodevelopmental disorders with or without other system involvement had pathogenic POGZ variants.
Stessman et al. (2016) found that knockdown of the POGZ ortholog 'row' in Drosophila resulted in impaired learning in a habituation paradigm. The 'row' gene shares only about 10% identity with human POGZ, but both contain a well-conserved (25% identity) central zinc finger domain.
In a girl with White-Sutton syndrome (WHSUS; 616364), the Deciphering Developmental Disorders Study (2015) identified a heterozygous de novo 1-bp deletion in the POGZ gene (chr1.151,378,156delG, GRCh37), resulting in frameshift. No functional studies were performed.
White et al. (2016) referred to this mutation as c.3354delC in exon 19, resulting in a frameshift and premature termination (Leu1119CysfsTer).
In a girl with White-Sutton syndrome (WHSUS; 616364), the Deciphering Developmental Disorders Study (2015) identified a heterozygous de novo A-to-T transversion at chromosome coordinate g.151,378,800 (chr1.151,378,800A-T, GRCh37) in the POGZ gene, predicted to result in a loss of function. No functional studies were performed.
White et al. (2016) referred to this mutation as a c.2711T-A transversion in exon 19, resulting in a Leu904-to-ter (L904X) substitution.
In a child with White-Sutton syndrome (WHSUS; 616364), White et al. (2016) identified a de novo heterozygous 1-bp duplication (c.2763dupC, NM_015100.3) in exon 19 of the POGZ gene, resulting in a frameshift and premature termination (Thr922HisfsTer22). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in publicly available databases, including the ExAC database. Functional studies were not performed, but the mutation was predicted to result in a loss of function.
In a child with White-Sutton syndrome (WHSUS; 616364), White et al. (2016) identified a de novo heterozygous c.833C-G transversion (c.833C-G, NM_015100.3) in exon 6 of the POGZ gene, resulting in a ser278-to-ter (S278X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in publicly available databases, including the ExAC database. Functional studies were not performed, but the mutation was predicted to result in a loss of function.
In a child with White-Sutton syndrome (WHSUS; 616364), White et al. (2016) identified a de novo heterozygous c.2935C-T transition (c.2935C-T, NM_015100.3) in exon 19 of the POGZ gene, resulting in an arg979-to-ter (R979X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in publicly available databases, including the ExAC database. Functional studies were not performed, but the mutation was predicted to result in a loss of function.
In a 5-year-old Chinese girl with White-Sutton syndrome (WHSUS; 616364), Tan et al. (2016) identified a de novo heterozygous 1-bp insertion (c.1277_1278insC) in exon 9 of the POGZ gene, resulting in a frameshift, premature termination, and truncated protein of 427 amino acids. The protein was truncated in the zinc finger domain. The mutation, which was found by next-generation sequencing of the POGZ gene in 764 patients with neurodevelopmental disorders, was confirmed by Sanger sequencing and filtered against the Exome Sequencing Project (ESP6500) and 1000 Genomes Project databases and an in-house exome database of about 500 individuals. Western blot analysis of patient blood cells showed the presence of a truncated protein and decreased levels of the wildtype protein.
In a 5-year-old girl with White-Sutton syndrome (WHSUS; 616364), Stessman et al. (2016) identified a de novo heterozygous c.2590C-T transition (c.2590C-T, NM_015100.3) in the POGZ gene, resulting in an arg864-to-ter (R864X) substitution. Functional studies of the variant and studies of patient cells were not performed.
In 2 unrelated patients with White-Sutton syndrome (WHSUS; 616364), Stessman et al. (2016) identified a de novo heterozygous c.3001C-T transition (c.3001C-T, NM_015100.3) in the POGZ gene, resulting in an arg1001-to-ter (R1001X) substitution. Functional studies of the variant and studies of patient cells were not performed.
In a 26-year-old man with White-Sutton syndrome (WHSUS; 616364), Stessman et al. (2016) identified a de novo heterozygous c.3847C-T transition (c.3847C-T, NM_015100.3) in the POGZ gene, resulting in a gln1283-to-ter (Q1283X) substitution. Functional studies of the variant and studies of patient cells were not performed.
In 2 unrelated patients with White-Sutton syndrome (WHSUS; 616364), Stessman et al. (2016) identified a de novo heterozygous 1-bp deletion in the POGZ gene, which the authors denoted as c.3456_3457del (c.3456_3457del, NM_015100.3), resulting in a frameshift and premature termination (Glu1154ThrfsTer4). Functional studies of the variant and studies of patient cells were not performed.
In a patient (PT17) with White-Sutton syndrome (WHSUS; 616364), Assia Batzir et al. (2020) identified a de novo heterozygous splice site mutation (c.460-2A-C, NM_015100.3) in intron 5 of the POGZ gene, which was predicted to affect all but one RefSeq-curated transcript of the gene.
Assia Batzir, N., Posey, J. E., Song, X., Coban Akdemir, Z., Rosenfeld, J. A., Brown, C. W., Chen, E., Holtrop, S. G., Mizerik, E., Nieto Moreno, M., Payne, K., Raas-Rothschild, An., Scott, R., Vernon, H. J., Zadeh, N., Baylor-Hopkins Center for Mendelian Genomics, Lupski, J. R., Reid Suton, V. Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome). Am. J. Med. Genet. 182A: 38-52, 2020. [PubMed: 31782611] [Full Text: https://doi.org/10.1002/ajmg.a.61380]
Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519: 223-228, 2015. [PubMed: 25533962] [Full Text: https://doi.org/10.1038/nature14135]
Gunther, M., Laithier, M., Brison, O. A set of proteins interacting with transcription factor Sp1 identified in a two-hybrid screening. Molec. Cell. Biochem. 210: 131-142, 2000. [PubMed: 10976766] [Full Text: https://doi.org/10.1023/a:1007177623283]
Hartz, P. A. Personal Communication. Baltimore, Md. 8/27/2012.
Nozawa, R.-S., Nagao, K., Masuda, H.-T., Iwasaki, O., Hirota, T., Nozaki, N., Kimura, H., Obuse, C. Human POGZ modulates dissociation of HP1-alpha from mitotic chromosome arms through Aurora B activation. Nature Cell Biol. 12: 719-727, 2010. [PubMed: 20562864] [Full Text: https://doi.org/10.1038/ncb2075]
Seki, N., Ohira, M., Nagase, T., Ishikawa, K., Miyajima, N., Nakajima, D., Nomura, N., Ohara, O. Characterization of cDNA clones in size-fractionated cDNA libraries from human brain. DNA Res. 4: 345-349, 1997. [PubMed: 9455484] [Full Text: https://doi.org/10.1093/dnares/4.5.345]
Stessman, H. A. F., Willemsen, M. H., Fenckova, M., Penn, O., Hoischen, A., Xiong, B., Wang, T., Hoekzema, K., Vives, L., Vogel, I., Brunner, H. G., van der Burgt, I., and 39 others. Disruption of POGZ is associated with intellectual disability and autism spectrum disorders. Am. J. Hum. Genet. 98: 541-552, 2016. [PubMed: 26942287] [Full Text: https://doi.org/10.1016/j.ajhg.2016.02.004]
Tan, B., Zou, Y., Zhang, Y., Zhang, R., Ou, J., Shen, Y., Zhao, J., Luo, X., Guo, J., Zeng, L., Hu, Y., Zheng, Y., Pan, Q., Liang, D., Wu, L. A novel de novo POGZ mutation in a patient with intellectual disability. J. Hum. Genet. 61: 357-359, 2016. [PubMed: 26763879] [Full Text: https://doi.org/10.1038/jhg.2015.156]
White, J., Beck, C. R., Harel, T., Posey, J. E., Jhangiani, S. N., Tang, S., Farwell, K. D., Powis, Z., Mendelsohn, N. J., Baker, J. A., Pollack, L., Mason, K. J., and 19 others. POGZ truncating alleles cause syndromic intellectual disability. Genome Med. 8: 3, 2016. Note: Electronic Article. [PubMed: 26739615] [Full Text: https://doi.org/10.1186/s13073-015-0253-0]