Alternative titles; symbols
HGNC Approved Gene Symbol: ZIC2
Cytogenetic location: 13q32.3 Genomic coordinates (GRCh38): 13:99,981,784-99,986,765 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q32.3 | Holoprosencephaly 5 | 609637 | Autosomal dominant | 3 |
Holoprosencephaly is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. Brown et al. (1998) reported that the human ZIC2 gene, a homolog of the Drosophila 'odd-paired' (opa) gene, maps to the region of chromosome 13 associated with holoprosencephaly (HPE5; 609637). The human ZIC2 gene was identified by defining a region of conserved synteny with the mouse genome, using several anonymous cDNA clones that had previously been assigned to chromosome 13q32. One mouse clone was shown to be a portion of Zic2, as reported by Aruga et al. (1996). The predicted human and mouse ZIC2 proteins contain 533 and 530 amino acids, respectively, and have an identical zinc finger domain.
Using in situ hybridization, Nagai et al. (1997) found that mouse Zic2 was expressed in early fetal brain, spinal cord, eye, and somites. At midgestation, Zic2 was expressed predominantly in thalamus, midbrain, cerebellum, spinal cord, all retinal layers and preciliary body, and primitive meninx and precartilage of limb mesenchyme. Brown et al. (1998) noted that this expression pattern was consistent with a major role in brain and distal limb development. Using Northern blot analysis of human tissues, Brown et al. (1998) detected expression of ZIC2 in fetal brain only.
Using 3 copies of the activator region-1 (AR1) in the upstream promoter of dopamine-1A receptor gene (D1A, or DRD1; 126449), Yang et al. (2000) cloned ZIC2 in a yeast 1-hybrid screen of a human brain cDNA library. The deduced 532-amino acid protein has an N-terminal zinc finger domain. The zinc finger domains of human and mouse ZIC2 are 100% identical, but the C-terminal domains differ substantially. Northern blot analysis of 8 human tissues detected ZIC2 expression in brain only. Within brain, transcripts of 3.2 and 3.5 kb were detected at high levels in cerebellum. Expression was much lower in all other brain regions examined except caudate, putamen, and substantia nigra, where ZIC2 expression was absent.
The AR1 region in the upstream promoter of the D1A gene contains partially overlapping binding sites for SP1 (189906) and AP2 (see TFAP2A; 107580) on opposite strands. Using gel mobility shift and reporter gene assays, Yang et al. (2000) found that human ZIC2 bound the AR1 sequence and repressed its expression. ZIC2 also significantly decreased expression of endogenous D1a in a mouse neuroblastoma cell line. ZIC2 efficiently blocked SP1 and SP3 (601804) binding to an AR1 probe and inhibited SP1- and SP3-mediated AR1 promoter activity. ZIC2 also displaced SP1 and SP2 binding to AR1 over time, leading to complete suppression of D1A promoter activity, suggesting that ZIC2 contains a repressor domain.
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 (600470) and ZIC2 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.
Herrera et al. (2003) found that mouse Zic2 was expressed in retinal ganglion cells (RGCs) with an uncrossed trajectory during the period when this subpopulation grew from the ventrotemporal retina toward the optic chiasm. Loss- and gain-of-function analyses indicated that Zic2 was necessary and sufficient to regulate RGC axon repulsion by cues at the optic chiasm midline. Moreover, expression of Zic2 correlated with the extent of binocularity in pigmented mouse, albino mouse, ferret, frog, and chicken. Herrera et al. (2003) concluded that ZIC2 is an evolutionarily conserved determinant of RGCs that project ipsilaterally.
Using yeast 2-hybrid, protein pull-down, and immunoprecipitation analyses, Ogawa et al. (2008) found that mouse Zic2 interacted with Rines (RNF180; 616015), a membrane-bound E3 ubiquitin ligase. Coexpression of Rines with the E2 ubiquitin-conjugating enzyme Ubch6 (UBE2E1; 602916) in mammalian cell lines caused Zic2 ubiquitination and proteasomal degradation.
Brown et al. (1998) determined that the ZIC2 gene contains 2 exons and spans about 4 kb.
The ZIC2 gene maps to chromosome 13q32 (Brown et al., 1998).
Brown et al. (1998) determined that heterozygous mutations in ZIC2 are associated with HPE5 (609637). Haploinsufficiency of ZIC2 is likely to cause the brain malformation seen in 13q deletion patients. Brown et al. (1998) used SSCP to screen for ZIC2 mutations in DNA samples from 150 patients with sporadic HPE and 63 patients with familial HPE. One sporadic patient showed a 56-bp head-to-tail repeat insertion in the first exon of the gene (603073.0001). In a second sporadic case, a 1-bp C insertion caused a frameshift that altered the last 90 amino acids, or approximately 20%, of the protein (603073.0002). In a third family with 2 sibs affected with HPE, Brown et al. (1998) determined that both had a 30-bp insertion in the third exon of ZIC2 (603073.0003). This insertion was a head-to-tail repeat and expanded the alanine tract normally present at that position from 15 to 25 alanine residues. In a fourth family with a single child affected with HPE, Brown et al. (1998) found a 7-bp deletion in the zinc finger region that destroyed the reading frame (603073.0004).
Since mutations in both ZIC2 and SHH (600725) can cause HPE, Brown et al. (1998) raised the question of whether they act in the same or different developmental pathways. They noted that ZIC2 expression differs from that of SHH in that ZIC2 message is seen in the dorsal neural tube and SHH functions in the ventral neural tube, suggesting that these 2 proteins may affect neural development in different ways. None of the patients with ZIC2 mutations had serious malformations of the face; facial malformation is a frequent occurrence with SHH mutations.
Brown et al. (2001) found 15 ZIC2 mutations within a cohort of 509 isolated holoprosencephaly cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, a C-terminal alanine tract expansion, occurred in 7 patients from 6 different families. In 3 of those families, the father was found to be apparently mosaic for the mutation. The authors hypothesized that this mutation may arise through errors in somatic recombination, an extremely unusual mutation mechanism.
By in vitro assay of HPE-associated mutant and wildtype ZIC2 protein constructs, Brown et al. (2005) determined that either a decrease or an increase in ZIC2-mediated transcriptional activity can produce a forebrain phenotype. In vitro analysis of ZIC2 proteins with different alanine tract length showed that a 25-alanine expansion had reduced DNA binding and transcriptional activity compared to wildtype ZIC2, whereas a shortened 2-alanine tract had increased DNA binding and transcriptional activity compared to wildtype.
Jobanputra et al. (2012) reported the detection of a complex chromosomal rearrangement, including duplication of a small region of chromosome 13q32 containing the ZIC2 gene, in a fetus referred for prenatal counseling. Ultrasound showed normal head circumference, and the child was born without holoprosencephaly and showed normal development at age 3 months. In addition, review of the phenotypes of 4 additional patients with duplications of 13q containing ZIC2 and 3 patients with supernumerary marker chromosomes derived from distal chromosome 13 indicated that none of the 8 patients had holoprosencephaly or brain malformations. However, most of these patients did have developmental delay, white matter or mild brain abnormalities such as temporal lobe hypoplasia or midbrain hypoplasia, and other congenital anomalies. Jobanputra et al. (2012) concluded that duplication of the distal region of chromosome 13, and in particular without duplication of ZIC2, is not associated with holoprosencephaly.
The kumba (Ku) allele of mouse Zic2 carries an inactivating missense mutation. Warr et al. (2008) found that 12.5-day postcoitum Zic2 Ku/Ku embryos had grossly abnormal cranial development. Most had exencephaly, and all showed abnormally spaced eyes ranging from hypotelorism to cyclopia. The remnants of forebrain were rostral of the eye and remained a single mass with no evidence of interhemispheric fissure. Experiments with compound Zic2 Ku and Shh mutant animals suggested that there is no direct genetic interaction between Zic2 and Shh. Molecular defects were seen at about 7.0 days postcoitum in the node and emerging mesendoderm of Zic2 Ku/Ku embryos, prior to induction of Shh signaling. Zic2 Ku/Ku embryos showed abnormalities at midgastrulation, with abnormalities at the organizer region (or node) and insufficient generation of anterior notochord precursors, leading to arrested development of the prechordal plate and anterior notochord by 9.5 days postcoitum. Warr et al. (2008) concluded that HPE5 is caused by a transient defect in the organizer region during gastrulation.
In a sporadic case of holoprosencephaly (HPE5; 609637), Brown et al. (1998) found a 56-bp head-to-tail repeat insertion in the first exon of the ZIC2 gene. This apparent de novo insertion was predicted to destroy the reading frame. The patient had extreme microcephaly at birth and semilobar HPE with monoventricle and agenesis of the corpus callosum by brain ultrasonography and magnetic resonance imaging. Only minor facial dysmorphic features were present. At 2 years of age, she was profoundly delayed developmentally.
In a male with alobar holoprosencephaly (HPE5; 609637) accompanied by hydrocephalus, Brown et al. (1998) found insertion of a single C in the ZIC2 gene, causing a frameshift that altered the last 99 amino acids, or approximately 20%, of the protein. The C insertion was not present in the parents or in an unaffected sib.
In a family with 2 sibs affected with holoprosencephaly (HPE5; 609637), Brown et al. (1998) found a 30-bp insertion in the third exon of ZIC2. The insertion represented a head-to-tail repeat and expanded the alanine tract normally present at that position from 15 to 25 alanine residues. The father was a mosaic carrier for the mutation, which had apparently arisen postzygotically. PCR with his lymphocyte DNA consistently showed a normal-sized allele as well as a faint band, which proved to be the expanded allele. The 2 affected children had alobar HPE and microcephaly and were profoundly delayed developmentally. Neither had severe facial malformation. The father, although not mentally retarded, was said to be of subnormal intelligence. He had a normal brain by computed tomography scan and no physical evidence of HPE.
In a child with holoprosencephaly (HPE5; 609637) with no major facial malformation, Brown et al. (1998) found a 7-bp deletion in the zinc finger region of the ZIC2 gene, destroying the reading frame. CT imaging of the brain showed alobar HPE. At 32 months of age, her developmental milestones were severely delayed.
In a newborn with sporadic holoprosencephaly (HPE5; 609637), Orioli et al. (2001) found deletion of nucleotides 860 and 861 in exon 1 in the zinc finger domain of the ZIC2 gene. It was not present in either parent. The patient presented with semilobar HPE, microcephaly, trigonocephaly, and a relatively nondysmorphic face.
In 2 half sisters with holoprosencephaly (HPE5; 609637) and partial rhombencephalosynapsis, Ramocki et al. (2011) identified a heterozygous 7-bp deletion (392_398del) in exon 1 of the ZIC2 gene, predicted to result in a frameshift and premature termination. One of the girls had macrocephaly and scaphocephaly, and the other had microcephaly. Both had severe mental retardation and motor disability. The mother did not carry the deletion in her peripheral blood, suggesting germline mosaicism. Although these findings suggested that rhombencephalosynapsis may be related to HPE, no ZIC2 mutations were identified in 11 additional cases of rhombencephalosynapsis. Guleria (2011) disagreed with the diagnosis of partial rhombencephalosynapsis in the patients reported by Ramocki et al. (2011), and suggested that the appearance of the contiguous cerebellar folial pattern likely resulted from a small posterior fossa and crowding of the structures. Ramocki et al. (2011) responded that the interpretation of neuroimaging regarding the diagnosis of partial rhombencephalosynapsis is controversial, and maintained that their patients were correctly diagnosed.
Aruga, J., Nagai, T., Tokuyama, T., Hayashizaki, Y., Okazaki, Y., Chapman, V. M., Mikoshiba, K. The mouse Zic gene family: homologues of the Drosophila pair-rule gene odd-paired. J. Biol. Chem. 271: 1043-1047, 1996. [PubMed: 8557628] [Full Text: https://doi.org/10.1074/jbc.271.2.1043]
Brown, L., Paraso, M., Arkell, R., Brown, S. In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation. Hum. Molec. Genet. 14: 411-420, 2005. [PubMed: 15590697] [Full Text: https://doi.org/10.1093/hmg/ddi037]
Brown, L. Y., Odent, S., David, V., Blayau, M., Dubourg, C., Apacik, C., Delgado, M. A., Hall, B. D., Reynolds, J. F., Sommer, A., Wieczorek, D., Brown, S. A., Muenke, M. Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum. Molec. Genet. 10: 791-796, 2001. [PubMed: 11285244] [Full Text: https://doi.org/10.1093/hmg/10.8.791]
Brown, S. A., Warburton, D., Brown, L. Y., Yu, C., Roeder, E. R., Stengel-Rutkowski, S., Hennekam, R. C. M., Muenke, M. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nature Genet. 20: 180-183, 1998. [PubMed: 9771712] [Full Text: https://doi.org/10.1038/2484]
Guleria, S. ZIC2 mutations are seen in holoprosencephaly and not partial rhombencephalosynapsis. (Letter) Am. J. Med. Genet. 155A: 2901 only, 2011. [PubMed: 21990207] [Full Text: https://doi.org/10.1002/ajmg.a.34282]
Herrera, E., Brown, L., Aruga, J., Rachel, R. A., Dolen, G., Mikoshiba, K., Brown, S., Mason, C. A. Zic2 patterns binocular vision by specifying the uncrossed retinal projection. Cell 114: 545-557, 2003. Note: Erratum: Cell 115: 125 only, 2003. [PubMed: 13678579] [Full Text: https://doi.org/10.1016/s0092-8674(03)00684-6]
Jobanputra, V., Burke, A., Kwame, A.-Y., Shanmugham, A., Shirazi, M., Brown, S., Warburton, P. E., Levy, B., Warburton, D. Duplication of the ZIC2 gene is not associated with holoprosencephaly. Am. J. Med. Genet. 158A: 103-108, 2012. [PubMed: 22105922] [Full Text: https://doi.org/10.1002/ajmg.a.34375]
Nagai, T., Aruga, J., Takada, S., Gunther, T., Sporle, R., Schughart, K., Mikoshiba, K. The expression of the mouse Zic1, Zic2, and Zic3 gene suggests an essential role for Zic genes in body pattern formation. Dev. Biol. 182: 299-313, 1997. [PubMed: 9070329] [Full Text: https://doi.org/10.1006/dbio.1996.8449]
Ogawa, M., Mizugishi, K., Ishiguro, A., Koyabu, Y., Imai, Y., Takahashi, R., Mikoshiba, K., Aruga, J. Rines/RNF180, a novel RING finger gene-encoded product, is a membrane-bound ubiquitin ligase. Genes Cells 13: 397-409, 2008. [PubMed: 18363970] [Full Text: https://doi.org/10.1111/j.1365-2443.2008.01169.x]
Orioli, I. M., Castilla, E. E., Ming, J. E., Nazer, J., Burle de Aguiar, M. J., Llerena, J. C., Muenke, M. Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly. Hum. Genet. 109: 1-6, 2001. [PubMed: 11479728] [Full Text: https://doi.org/10.1007/s004390100537]
Ramocki, M. B., Scaglia, F., Stankiewicz, P., Belmont, J. W., Jones, J. Y., Clark, G. D. Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2. Am. J. Med. Genet. 155A: 1574-1580, 2011. [PubMed: 21638761] [Full Text: https://doi.org/10.1002/ajmg.a.34029]
Ramocki, M., Scaglia, F., Jones, J., Clark, G. Rhombencephalosynapsis is a malformation deserving of further study. (Letter) Am. J. Med. Genet. 155A: 2902 only, 2011.
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]
Warr, N., Powles-Glover, N., Chappell, A., Robson, J., Norris, D., Arkell, R. M. Zic2-associated holoprosencephaly is caused by a transient defect in the organizer region during gastrulation. Hum. Molec. Genet. 17: 2986-2996, 2008. [PubMed: 18617531] [Full Text: https://doi.org/10.1093/hmg/ddn197]
Yang, Y., Hwang, C. K., Junn, E., Lee, G., Mouradian, M. M. ZIC2 and Sp3 repress Sp1-induced activation of the human D(1A) dopamine receptor gene. J. Biol. Chem. 275: 38863-38869, 2000. [PubMed: 10984499] [Full Text: https://doi.org/10.1074/jbc.M007906200]