Disease relevance of ZIC2

• Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly [1].
• Genetic variants in ZIC1, ZIC2, and ZIC3 are not major risk factors for neural tube defects in humans [2].
• The ZIC2 zinc finger gene was overexpressed in endometrial cancers with positive nodes versus those with negative nodes [3].
• The minimal deletion interval associated with the Dandy-Walker malformation (DWM) was narrowed to the 13q32.2-33.2 region, in which the ZIC2 and ZIC5 genes proposed as underlying various CNS malformations are mapped [4].

High impact information on ZIC2

• Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired [5].
• In sera from 23 normal adults, no antibody was detected against SOX group B or ZIC2 proteins except for one individual with low-titer anti-SOX2 antibody [6].
• This region of ZIC2 contains an alanine-tract, and expansion of this domain is associated with HPE [7].
• Analysis of these mutations suggests that either a decrease or an increase in ZIC2 mediated transcriptional activity can produce a forebrain phenotype [7].
• In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation [7].

Chemical compound and disease context of ZIC2

• Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination [8].

Biological context of ZIC2

• We identified three novel mutations: two were missense mutations of the SHH gene (Cys183-->Phe; His140-->Pro); the third mutation was a 2-bp deletion in the zinc-finger region of the ZIC2 gene [1].
• We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes [8].
• Mutation in human ZIC2, a zinc finger protein homologous to Drosophila odd-paired, causes holoprosencephaly (HPE), which is a common, severe malformation of the brain in humans [9].
• Electrophoretic mobility shift assays confirmed the presence of a binding site for Zic1 and Zic2 in the -136/-125 region [10].
• Stepwise exchange from complex I to complex II depended on phosphorylation of Zic2 by DNA-PK and poly-(ADP-ribose) polymerase [11].

Anatomical context of ZIC2

• The central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect (one case) [8].
• Zic2 and D(1A) genes have reciprocal brain regional distributions; Zic2 is expressed primarily in the cerebellum, and D(1A) is highly expressed in corpus striatum [12].
• Ectopic expression of Zic1 and Zic2 in U87 cells also trans-stimulated the expression of the endogenous gene, increasing the amount of apolipoprotein E produced by glial cells [10].
• By isolating specific subregions and layers of the thalamus, we identified a set of transcription factors, including Zic2, Islet1, and Six3, the unique distribution profiles of which differentiated the lateral geniculate nucleus (LGN) from the associated perigeniculate nucleus [13].

Associations of ZIC2 with chemical compounds

• In ZIC2 we identified a deletion of one codon that encodes an alanine residue located in the amino terminal alanine stretch of the protein [2].
• ZIC2 and Sp3 repress Sp1-induced activation of the human D1A dopamine receptor gene [12].
• Possible association of NTDs with a polyhistidine tract polymorphism in the ZIC2 gene [14].
• While we did not find ZIC2 mutations in these patients, we did find some evidence of a possible association between a histidine tract polymorphism in ZIC2 and NTDs [14].
• Seroreactivity against either SOX1 or ZIC2 correlated with younger age, lower lactate dehydrogenase levels, and better response to initial therapy [15].

Physical interactions of ZIC2

• Transcription factors Zic1 and Zic2 bind and transactivate the apolipoprotein E gene promoter [10].

Other interactions of ZIC2

• Our data indicate that ZIC1, ZIC2, and ZIC3 are not major risk factors for NTD in humans [2].
• In our cohort of 200 patients, 34 heterozygous mutations were identified, 24 of them being novel ones: 13 out of 17 in the Sonic hedgehog gene (SHH); 4 out of 7 in ZIC2; and 7 out of 8 in SIX3 [16].
• No sequence changes were detected in SHH, ZIC2, and PTC [17].
• Frequency of SOX Group B (SOX1, 2, 3) and ZIC2 antibodies in Turkish patients with small cell lung carcinoma and their correlation with clinical parameters [15].
• ZIC2 is mutated in human holoprosencephaly (HPE), a severe defect in brain hemisphere separation, and these results strengthen the suggestion that increased Nodal-related activity is a cause of HPE [18].

Analytical, diagnostic and therapeutic context of ZIC2

• First, phenotype producing mutations in human and in mouse ZIC2 were mimicked and secondly, a comparative sequence analysis of the C-terminal was carried out [7].
• Since human ZIC2 haploinsufficiency is a cause of holoprosencephaly, the Zic2kd/kd mice are regarded as an animal model for holoprosencephaly in humans [19].

References