Alternative titles; symbols
HGNC Approved Gene Symbol: ZNF462
Cytogenetic location: 9q31.2 Genomic coordinates (GRCh38): 9:106,860,158-107,013,634 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q31.2 | Weiss-Kruszka syndrome | 618619 | Autosomal dominant | 3 |
The ZNF462 gene encodes a transcription factor that is believed to have an important role in embryonic development and chromatin remodeling (summary by Kruszka et al., 2019).
By sequencing clones obtained from a size-fractionated fetal human brain cDNA library, Nagase et al. (2001) cloned ZNF462, which they designated KIAA1803. The deduced 1,299-amino acid protein has 9 C2H2 zinc finger motifs. RT-PCR ELISA detected KIAA1803 in all adult and fetal tissues and specific adult brain regions examined.
By Western blot analysis, Wang et al. (2017) showed that Zfp462 was expressed in mouse heart, liver, lung, kidney, muscle, and whole brain. Highest expression was in brain, and Zfp462 expression was more abundant in cortex and hippocampus than other brain regions.
Hartz (2017) mapped the ZNF462 gene to chromosome 9q31.2 based on an alignment of the ZNF462 sequence (GenBank AL359561) with the genomic sequence (GRCh38).
By immunoprecipitation analysis, Wang et al. (2017) showed that Zfp462 interacted with Pbx1 (176310), a cofactor of Hoxb8 (142963), in mouse brain.
In 4-affected members of a 4-generation family (family 1) with Weiss-Kruszka syndrome (WSKA; 618619), Weiss et al. (2017) identified a heterozygous nonsense mutation in the ZNF462 gene (R1263X; 617371.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, with evidence of variable expressivity. Three additional unrelated patients with a similar phenotype were found to carry de novo heterozygous loss-of-function mutations in the ZNF462 gene (see, e.g., 617371.0002-617371.0003). Functional studies of the variants and studies of patient cells were not performed, but all variants were predicted to result in a loss of function and haploinsufficiency. The authors noted that the ZNF462 gene is highly conserved in most mammals and is intolerant of loss-of-function variants based on databases of genetic variation.
In 14 unrelated patients with WSKA, Kruszka et al. (2019) identified heterozygous loss-of-function mutations in the ZNF462 gene (see, e.g., 617371.0004-617371.0007). The patients were diagnosed by whole-exome or whole-genome sequencing in multiple research and commercial labs, and 9 were found through GeneMatcher. Most of the mutations occurred de novo, but there was one instance of paternal transmission from a mildly affected father and another instance of maternal transmission from an unaffected mother who was mosaic for the mutation. Most of the mutations occurred in exon 3, which makes up 54% of the coding region. Functional studies of the variants and studies of patient cells were not performed, but all variants were predicted to result in ZNF462 haploinsufficiency.
Wang et al. (2017) found that Zfp462 -/- mice underwent prenatal death. Zfp462 +/- mice showed reduced Zfp462 expression and delayed postnatal development, including brain development, compared with wildtype. Protein expression of Pbx1 and Hoxb8 was decreased in Zfp462 +/- mice. Zfp462 +/- mice exhibited anxiety-like behaviors with excessive self-grooming, which could be attenuated by treatment with the anti-anxiety drug imipramine.
In 4-affected members of a 4-generation family (family 1) with Weiss-Kruszka syndrome (WSKA; 618619), Weiss et al. (2017) identified a heterozygous c.3787C-T transition (c.3787C-T, NM_021224.5) in exon 3 of the ZNF462 gene, resulting in an arg1263-to-ter (R1263X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, with evidence of variable expressivity. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency.
In a 2-year-old boy (patient 2) with Weiss-Kruszka syndrome (WSKA; 618619) Weiss et al. (2017) identified a de novo heterozygous c.2979_2980delinsA mutation (c.2979_2980delinsA, NM_021224.5) in exon 3 of the ZNF462 gene, resulting in a frameshift and premature termination (Val994TrpfsTer147). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and haploinsufficiency.
In a 9-year-old boy (patient 6) with Weiss-Kruszka syndrome (WSKA; 618619), Weiss et al. (2017) identified a de novo heterozygous 1-bp deletion (c.5145delC, NM_021224.5) in exon 3 of the ZNF462 gene, resulting in a frameshift and premature termination (Tyr1716ThrfsTer28). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency.
In a 10-year-old boy (patient 2) with Weiss-Kruszka syndrome (WSKA; 618619), Kruszka et al. (2019) identified a de novo heterozygous 1-bp deletion (c.2542delT) in exon 3 of the ZNF462 gene, resulting in a frameshift and premature termination (Cys848ValfsTer66). The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency.
In a 14-year-old girl (patient 5) of Latin American descent with Weiss-Kruszka syndrome (WSKA; 618619), Kruszka et al. (2019) identified a heterozygous c.763C-T transition (c.763C-T, NM_021224.5) in exon 3 of the ZNF462 gene, resulting in an arg255-to-ter (R255X) substitution. The mutation was inherited from her father who had milder but similar features and required surgery for ptosis. The mutation was found by whole-genome sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency.
In a 2-year-old boy (patient 8) with Weiss-Kruszka syndrome (WSKA; 618619), Kruszka et al. (2019) identified a de novo heterozygous 1-bp duplication (c.882dupC, NM_021224.5) in exon 3 of the ZNF462 gene, resulting in a frameshift and premature termination (Ser295GlnfsTer64). The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency.
In a 15-year-old boy (patient 9) with Weiss-Kruszka syndrome (WSKA; 618619), Kruszka et al. (2019) identified a de novo heterozygous c.4165C-T transition (c.4165C-T, NM_021224.5) in exon 3 of the ZNF462 gene, resulting in a gln1389-to-ter (Q1389X) substitution. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency.
Hartz, P. A. Personal Communication. Baltimore, Md. 2/27/2017.
Kruszka, P., Hu, T., Hong, S., Signer, R., Cogne, B., Isidor, B., Mazzola, S. E., Giltay, J. C., van Gassen, K. L. I., England, E. M., Pais, L., Ockeloen, C. W., and 20 others. Phenotype delineation of ZNF462 related syndrome. Am. J. Med. Genet. 179: 2075-2082, 2019. [PubMed: 31361404] [Full Text: https://doi.org/10.1002/ajmg.a.61306]
Nagase, T., Nakayama, M., Nakajima, D., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 8: 85-95, 2001. [PubMed: 11347906] [Full Text: https://doi.org/10.1093/dnares/8.2.85]
Wang, B., Zheng, Y., Shi, H., Du, X., Zhang, Y., Wei, B., Luo, M., Wang, H., Wu, X., Hua, X., Sun, M., Xu, X. Zfp462 deficiency causes anxiety-like behaviors with excessive self-grooming in mice. Genes Brain Behav. 16: 296-307, 2017. [PubMed: 27621227] [Full Text: https://doi.org/10.1111/gbb.12339]
Weiss, K., Wigby, K., Fannemel, M., Henderson, L. B., Beck, N., Ghali, N., DDD Study, Anderlid, B.-M., Lundin, J., Hamosh, A., Jones, M. C., Ghedia, S., Muenke, M., Kruszka, P. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. Europ. J. Hum. Genet. 25: 946-951, 2017. [PubMed: 28513610] [Full Text: https://doi.org/10.1038/ejhg.2017.86]