Alternative titles; symbols
HGNC Approved Gene Symbol: ZIC1
Cytogenetic location: 3q24 Genomic coordinates (GRCh38): 3:147,409,365-147,416,719 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q24 | ?Craniosynostosis 6 | 616602 | Autosomal dominant | 3 |
| Structural brain anomalies with impaired intellectual development and craniosynostosis | 618736 | Autosomal dominant | 3 |
In the mouse, Aruga et al. (1994) cloned a gene, which they named zic (for zinc finger protein of the cerebellum), after screening a lambda gt11 mouse cerebellar cDNA library. The putative open reading frame is 1,344 nucleotides encoding 447 amino acids and is preceded by 530 nucleotides of a 5-prime untranslated region. Northern blot hybridization studies failed to demonstrate zic expression in any tissues other than nervous tissue. Within the central nervous system, the highest level of expression was in the cerebellum, whereas the olfactory bulb, diencephalon, and brainstem showed only low levels of zic expression. The zic gene has significant homology to the zinc finger domain of the Caenorhabditis elegans tra1 gene, the Drosophila cubitus interruptus dominant gene, and the human GLI oncogene (165220). In situ hybridization demonstrated restricted expression of zic in granule cells and their putative precursors. It is also expressed in the dorsal half of the neural tube at early embryonic stages. Aruga et al. (1994) speculated that zic encodes a nuclear factor involved in differentiation in early development, as well as in the maintenance of the phenotypic properties of the cerebellar granule cells.
The ZIC is a zinc finger protein that displays a highly restricted expression pattern in the adult and developing mouse cerebellum and is highly homologous to the Drosophila pair-rule gene Opa. To clarify the mechanism for the development of the human cerebellum and the possible involvement of ZIC in human nervous system diseases, Yokota et al. (1996) isolated human ZIC cDNA and examined its expression by using monoclonal antibody against recombinant ZIC protein. The nucleotide sequence of human ZIC cDNA is 85% homologous to that the mouse zic gene. Its putative amino acid sequence is highly conserved (more than 99%) except for substitution of only 2 amino acid residues. The human ZIC protein was immunohistochemically detected in the nuclei of the cerebellar granule cell lineage from the progenitor cells of the external germinal layer to the postmigrated cells of the internal granular layer. Furthermore, ZIC protein was detected in medulloblastoma (26 of 29 cases), whereas none of 70 other tumors examined, including primitive neuroectodermal tumors, expressed this protein. These findings suggested that ZIC is a potential biomarker for medulloblastoma as well as the human cerebellar granule cell lineage.
Using a yeast 1-hybrid screen with the proximal region of the APOE (107741) promoter as bait, Salero et al. (2001) isolated cDNAs encoding the ZIC1 and ZIC2 (603073) transcription factors. Electrophoretic mobility shift and mutational analyses identified binding sites in the -136 to -125, -65 to -54, and -185 to -174 regions of the APOE promoter. Luciferase reporter analysis showed that the ZIC proteins stimulate potent transcriptional activation of APOE through these binding sites.
In mouse embryos, Twigg et al. (2015) detected a localized domain of Zic1 expression at embryonic days 11.5 to 12.5 in a region overlapping the supraorbital regulatory center, which patterns the coronal suture.
By fluorescence in situ hybridization, Yokota et al. (1996) mapped the human ZIC1 gene to chromosome 3q24.
Dandy-Walker malformation (DWM; 220200) is a common but poorly understood congenital cerebellar malformation in humans. Through mapping of 3q2 interstitial deletions in several individuals with DWM, Grinberg et al. (2004) defined the critical region associated with DWM, encompassing 2 ZIC genes, ZIC1 and ZIC4 (608948). Mice with a heterozygous deletion of these 2 linked genes were found to have a phenotype that closely resembles DWM, providing a mouse model for this malformation.
Structural Brain Anomalies with Impaired Intellectual Development and Craniosynostosis
In a 13-year-old boy with bicoronal synostosis, abnormal configuration of ventricles and corpus callosum on MRI, and marked psychomotor retardation with autistic features (BAIDCS; 618736), who was negative for mutation in the craniosynostosis-associated genes FGFR2 (176943), FGFR3 (134934), and TWIST1 (601622), Twigg et al. (2015) performed whole-genome sequencing and identified heterozygosity for a de novo nonsense mutation in the ZIC1 gene (S388X; 600470.0001). Mutant mRNA was detected in fibroblasts from this patient, indicating escape from nonsense-mediated decay. Screening for ZIC1 mutations in a panel of 307 probands with synostosis affecting any combination of sutures identified 1 patient with a different nonsense mutation (E402X; 600470.0002); later exome sequencing identified another patient from that panel with the E402X mutation, which was present in mosaic state. Both patients displayed bicoronal synostosis with severe brachycephaly, and both had a learning disability, which was milder in the mosaic patient. Analysis of samples from 3 additional patients who exhibited coronal synostosis as well as significant learning disability revealed another nonsense mutation in ZIC1 in 1 patient (Q389X; 600470.0003). In a Xenopus embryo assay, nonsense mutations were associated with altered and/or enhanced expression of engrailed-2 (EN2; 131310). These results and detection of expression in the supraorbital regulatory center of mouse embryos led Twigg et al. (2015) to conclude that ZIC1 plays a role in early cranial suture development.
In 2 sibs with BAIDCS, Vandervore et al. (2018) identified heterozygosity for a frameshift mutation in ZIC1 (600470.0005). Neither parent had evidence of the mutation by whole-exome sequencing (100 and 108 reads), suggesting that gonadal mosaicism for the mutation was present in one of the parents. Expression of the mutated allele was detected in patient fibroblasts by RT-PCR, evidence that the mutant mRNA did not undergo nonsense-mediated decay and probably generates an abnormal protein.
Craniosynostosis 6
In affected members of a 3-generation family with bicoronal synostosis or calvarial abnormality (CRS6; 616602), Twigg et al. (2015) identified heterozygosity for a missense mutation in ZIC1 (G400R; 600470.0004). In a Xenopus embryo assay, missense mutations were associated with altered and/or enhanced expression of engrailed-2 (EN2; 131310). These results and detection of expression in the supraorbital regulatory center of mouse embryos led Twigg et al. (2015) to conclude that IC1 plays a role in early cranial suture development.
In a 13-year-old boy (patient 1) with bicoronal synostosis and marked mental retardation with autistic features (BAIDCS; 618736), who also exhibited scoliosis and extensive spina bifida occulta, Twigg et al. (2015) identified heterozygosity for a de novo c.1163C-A transversion (c.1163C-A, NM_003412.3) in exon 3 of the ZIC1 gene, resulting in a ser388-to-ter (S388X) substitution in the fifth zinc finger. The mutation was not found in his unaffected parents. Mutant mRNA was detected in fibroblasts, indicating escape from nonsense-mediated decay. The patient had no language and only limited communication using signs.
In a 36-year-old woman with bicoronal synostosis and moderate to severe learning disability (BAIDCS; 618736), Twigg et al. (2015) identified heterozygosity for a de novo c.1204G-T transversion (c.1204G-T, NM_003412.3) in exon 3 of the ZIC1 gene, resulting in a glu402-to-ter (E402X) substitution in the fifth zinc finger. The mutation was not found in her unaffected parents. The patient lived in a supervised residential accommodation and was able to communicate in short sentences and manage personal grooming. In an unrelated 8-year-old boy with bicoronal synostosis, the E402X mutation was present in mosaic state: the mutation was not detected in DNA from scalp fibroblasts, but was identified in 34% of reads from exome sequencing of DNA from blood. The boy also displayed a patent metopic suture and wormian bone in the anterior fontanel, as well as an ossification defect of the sagittal suture, and he developed progressive turricephaly requiring surgical correction. Twigg et al. (2015) noted that intellectual disability was milder in the mosaic patient: he had mild developmental delay with speech dysfluency, and attended a normal school where he received 1:1 educational support because of delayed learning.
In a 4-year-old boy with bicoronal synostosis, partial right lambdoid synostosis, and significant learning difficulties (BAIDCS; 618736), Twigg et al. (2015) identified heterozygosity for a c.1165C-T transition (c.1165C-T, NM_003412.3) in exon 3 of the ZIC1 gene, resulting in a gln389-to-ter (Q389X) substitution in the fifth zinc finger. Brain MRI revealed short corpus callosum, enlarged lateral ventricles, peaked tentorium, hypoplastic pons, prominent cerebellar folia, and enlarged foramen magnum with signal void near the cervical cord. He had ataxic speech and gait and had been diagnosed with autistic spectrum disorder and attention deficit-hyperactivity disorder.
In 5 affected members of a 3-generation family with bicoronal synostosis and mild learning disabilities (CRS6; 616602), Twigg et al. (2015) identified heterozygosity for a c.1198G-C transversion (c.1198G-C, NM_003412.3) in exon 3 of the ZIC1 gene, resulting in a gly400-to-arg (G400R) substitution at a highly conserved residue in the fifth zinc finger. The mutation segregated with disease in the family and was not found in more than 120,000 alleles in the ExAC database. The proband and a male cousin exhibited bicoronal synostosis, whereas the proband's half-brother had Dandy-Walker malformation (see 220200). The proband's mother had brachycephaly and delayed closure of the anterior fontanel, whereas her affected sister (mother of the affected male cousin) displayed plagiocephaly. All 5 affected individuals had mild learning disabilities. Twigg et al. (2015) noted that the deceased maternal grandfather had high forehead, facial asymmetry, and hearing deficits, suggesting that his 2 affected daughters had inherited the G400R mutation from him.
In 2 Dutch sibs with structural brain anomalies and impaired intellectual development (BAIDCS; 618736), Vandervore et al. (2018) detected heterozygosity for a frameshift mutation (NM_003412.3, c.1214_1215delinsCCACCATCGTG) (Pro406fs) in exon 3 of the ZIC1 gene. The mutation was described as a deletion/insertion (c.1214_1215delinsCCACCATCGTG) and also as an insertion (c.1214_1215insCCACCATCGTG). Whole-exome and Sanger sequencing in the parents did not detect the mutation, indicating gonadal mosaicism. The mutation was absent from public sequence databases. Expression of the mutated allele was detected in patient fibroblasts by RT-PCR, evidence that the mutant mRNA did not undergo nonsense-mediated decay and probably generates an abnormal protein. Both sibs had agenesis of the corpus callosum, brachycephaly with reduced volume of the posterior fossa, and prominent pontocerebellar abnormality with partial fusion of cerebellar hemispheres (rhombencephalosynapsis) in one. Craniosynostosis was not present at birth; in the younger sib, cranial sutures were closed at the age of 8 months.
Aruga, J., Yokota, N., Hashimoto, M., Furuichi, T., Fukuda, M., Mikoshiba, K. A novel zinc finger protein, Zic, is involved in neurogenesis, especially in the cell lineage of cerebellar granule cells. J. Neurochem. 63: 1880-1890, 1994. [PubMed: 7931345] [Full Text: https://doi.org/10.1046/j.1471-4159.1994.63051880.x]
Grinberg, I., Northrup, H., Ardinger, H., Prasad, C., Dobyns, W. B., Millen, K. J. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nature Genet. 36: 1053-1055, 2004. [PubMed: 15338008] [Full Text: https://doi.org/10.1038/ng1420]
Salero, E., Perez-Sen, R., Aruga, J., Gimenez, C., Zafra, F. Transcription factors Zic1 and Zic2 bind and transactivate the apolipoprotein E gene promoter. J. Biol. Chem. 276: 1881-1888, 2001. [PubMed: 11038359] [Full Text: https://doi.org/10.1074/jbc.M007008200]
Twigg, S. R. F., Forecki, J., Goos, J. A. C., Richardson, I. C. A., Hoogeboom, A. J. M., van den Ouweland, A. M. W., Swagemakers, S. M. A., Lequin, M. H., Van Antwerp, D., McGowan, S. J., Westbury, I., Miller, K. A., Wall, S. A., WGS500 Consortium, Mathijssen, I. M. J., Pauws, E., Merzdorf, C. S., Wilkie, A. O. M. Gain-of-function mutations in ZIC1 are associated with coronal craniosynostosis and learning disability. Am. J. Hum. Genet. 97: 378-388, 2015. [PubMed: 26340333] [Full Text: https://doi.org/10.1016/j.ajhg.2015.07.007]
Vandervore, L. V., Schot, R., Hoogeboom, A. J. M., Lincke, C., de Coo, I. F., Lequin, M. H., Dremmen, M., van Unen, L. M. A., Saris, J. J., Jansen, A. C., van Slegtenhorst, M. A., Wilke, M., Mancini, G. M. S. Mutated zinc finger protein of the cerebellum 1 leads to microcephaly, cortical malformation, callosal agenesis, cerebellar dysplasia, tethered cord and scoliosis. Europ. J. Med. Genet. 61: 783-789, 2018. [PubMed: 30391508] [Full Text: https://doi.org/10.1016/j.ejmg.2018.10.018]
Yokota, N., Aruga, J., Takai, S., Yamada, K., Hamazaki, M., Iwase, T., Sugimura, H., Mikoshiba, K. Predominant expression of human Zic in cerebellar granule cell lineage and medulloblastoma. Cancer Res. 56: 377-383, 1996. [PubMed: 8542595]