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Abstract Zic family member ZIC4 is a transcription factor that has been shown to be silenced in several cancers. However, understanding the regulation and function of ZIC4 in pediatric choroid plexus tumors (CPTs) remained limited. This study employed data mining and bioinformatics analysis to investigate the DNA methylation status of ZIC4 in CPTs and its correlation with patient survival. Our results unveiled ZIC4 methylation as a segregating factor, dividing CPT cohorts into two clusters, with hyper-methylation linked to adverse prognosis. Hyper-methylation of ZIC4 was confirmed in a choroid plexus carcinoma-derived cell line (CCHE-45) by bisulfite sequencing. Furthermore, our study demonstrated that demethylating agent and a histone methyltransferase inhibitor could reverse ZIC4 silencing. RNA sequencing and proteomic analysis showed that ZIC4 over-expression influenced genes and proteins involved in immune response, antigen processing and presentation, endoplasmic reticulum stress, and metabolism. Functionally, re-expressing ZIC4 negatively impacted cell proliferation and migration. Ultimately, these findings underscore ZIC4 hyper-methylation as a prognostic marker in CPTs and shed light on potential mechanisms underlying its tumor suppressor role in CPC. This insight paves the way for novel therapeutic targets in treating aggressive CPTs.

Zic family member ZIC4 is a transcription factor that has been shown to be silenced in several cancers. However, understanding the regulation and function of ZIC4 in pediatric choroid plexus tumors (CPTs) remained limited. This study employed data mining and bioinformatics analysis to investigate the DNA methylation status of ZIC4 in CPTs and its correlation with patient survival. Our results unveiled ZIC4 methylation as a segregating factor, dividing CPT cohorts into two clusters, with hyper-methylation linked to adverse prognosis. Hyper-methylation of ZIC4 was confirmed in a choroid plexus carcinoma-derived cell line (CCHE-45) by bisulfite sequencing. Furthermore, our study demonstrated that demethylating agent and a histone methyltransferase inhibitor could reverse ZIC4 silencing. RNA sequencing and proteomic analysis showed that ZIC4 over-expression influenced genes and proteins involved in immune response, antigen processing and presentation, endoplasmic reticulum stress, and metabolism. Functionally, re-expressing ZIC4 negatively impacted cell proliferation and migration. Ultimately, these findings underscore ZIC4 hyper-methylation as a prognostic marker in CPTs and shed light on potential mechanisms underlying its tumor suppressor role in CPC. This insight paves the way for novel therapeutic targets in treating aggressive CPTs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: The caudal fin of teleosts is characterized by dorsoventral symmetry. Despite this external morphology, the principal rays of this appendage connect to bones below the notochord, indicating the ventral (hypochordal) identity of this organ. Results: Here, we report that this typical architecture of the caudal fin is not fully conserved in the platyfish (Xiphophorus maculatus) and the guppy (Poecilia reticulata), representatives of the Poeciliidae family. We show that in these species, 3–4 principal rays connect to bones above the notochord, suggesting an epichordal contribution. Consistently, as examined in platyfish, dorsal identity genes zic1/4 were highly expressed in these rays, providing molecular evidence of their epichordal origin. Developmental analysis revealed that the earliest rays above the notochord emerge at the 10‐ray stage of fin morphogenesis. In contrast to zebrafish and medaka, platyfish and guppies display a mirrored shape of dorsal and ventral processes of the caudal endoskeleton. Our study suggests that an ancestral bauplan expanded in poeciliids by advancing its symmetrical pattern. Conclusion: The platyfish evolved a fin architecture with the epichordal origin of its upper principal rays and a high level of symmetry in the caudal endoskeleton. This innovative architecture highlights the adaptation of the teleost skeleton. Key Findings: In platyfish, principal rays of the caudal fin are associated with endoskeletal elements not only below but also above the notochord.Dorsal identity markers zic1/4 are highly expressed in the three uppermost principal rays.The epichordal principal rays begin to form at the developmental stage with 10 caudal rays.The caudal fin of platyfish displays a striking internal symmetry of the endoskeleton. [ABSTRACT FROM AUTHOR]

Abstract Background Cerebellar degeneration as a consequence of a malignancy is a rare condition most commonly related to the presence of anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. In recent years, several reports have indicated Zinc-finger protein 4 (Zic4) antibodies being associated with paraneoplastic cerebellar degeneration (PCD) in patients with small cell lung carcinoma. However, the prevalence and the significance of Zic4-antibodies may be underestimated due to their co-occurrence with more frequent antibodies such as anti-Hu. A literature review of isolated Zic4 mediated paraneoplastic syndromes yielded 14 cases reporting mainly benign clinical courses when treated early. Case presentation We present the case of a 67-year-old woman with progressive Zic4 antibody mediated PCD and rhombencephalitis. Immunomodulatory treatment, including intravenous methylprednisolone, plasmaphereses, and intravenous immunoglobulin (IVIG) was administered. Small cell lung cancer (SCLC) was detected, lobectomy performed and cyclophosphamide started. Despite this considerable therapeutic effort, rhombencephalitis led to defiant dysautonomia. Conclusion Paraneoplastic syndromes related to isolated Zic4 antibodies are rare and typically show a benign clinical course. Here, we present the first case of a rapidly progressive isolated Zic4 associated PCD and rhombencephalitis. Despite considerable therapeutic efforts, the patient passed away on autonomic dysfunction, highlighting the significance of Zic4 associated disease.

Background: Even within the most populous countries in the Middle East, such as Iran, autoimmune encephalitis cases have been rarely reported. Objective: We aimed to describe the demographic, clinical, and paraclinical characteristics of Iranian patients with autoimmune encephalitis positive for anti-neuronal autoantibodies. Methods: This cross-sectional study included all patients diagnosed with autoimmune encephalitis and referred to our hospital, in Isfahan, Iran, from March 2016 to May 2020. Patients' demographic, clinical, laboratory, radiological, and electroencephalographic features were obtained from their medical records. Results: We identified a total of 39 (21 females, 53.8%) patients with autoimmune encephalitis (mean age = 34.9 ± 12.8 years). The most commonly detected antibody was anti-NMDAR (n = 26, 66.7%), followed by anti-GABABR (n = 8, 20.5%), anti-Zic4 (n = 4, 10.3%), and anti-GAD65 (n = 1, 2.6%) antibodies, in descending order of frequency. Two anti-NMDAR-positive patients had a history of systemic lupus erythematosus (SLE), and four had a prior history of herpes simplex encephalitis. Clinical presentations in patients positive for anti-Zic4 antibodies included cognitive decline (n = 4, 100%), seizures (n = 3, 75%), parkinsonism (n = 1, 25%), and stiff-person syndrome (n = 1, 25%). Conclusion: This was the first case series of Iranian patients with autoimmune encephalitis with some interesting observations, including SLE-associated anti-NMDAR encephalitis, as well as an unusual concurrence of anti-Zic4 antibody positivity and cognitive problems, seizures, parkinsonism, and stiff-person syndrome. [ABSTRACT FROM AUTHOR]

BackgroundEpigenetic dysregulation is one of the postulated underlying mechanisms of neural tube defects (NTDs). Polycyclic aromatic hydrocarbons (PAHs), a group of environmental pollutants that are reported as a risk factor of NTDs, may cause decreased genome-wide DNA methylation. With DNA extracted from neural tissues, this study identified gene(s) whose hypomethylation was related to elevated risk for NTDs and examined whether its hypomethylation is related to PAH exposure.ResultsUsing data profiled by Infinium HumanMethylation450 BeadChip array from 10 NTD cases and eight controls, ZIC4, CASP8, RAB32, RARA, and TRAF6 were identified to be the top five genes in NTD-related hypomethylated gene families. Among all identified genes, ZIC4 had the largest number of differently methylated CpG sites (n = 13) in the promoter region and 5′ UTR. Significantly decreased methylation in the ZIC4 promoter region and 5′ UTR was verified in an independent cohort of 80 cases and 32 controls (p < 0.001) utilizing the Sequenom EpiTYPER platform. Hypomethylation of ZIC4 was associated with a higher risk of NTDs [adjusted OR = 1.08; 95% confidence interval (CI): 1.03, 1.13] in a logistic regression model. Mean methylation levels in the promoter region and 5′ UTR of ZIC4 tended to be inversely associated with levels of high-molecular-weight PAHs in fetal liver among NTD fetuses (β [95% CI]: −0.045 [−0.091, 0.001], p = 0.054). Six and three CpG sites in the ZIC4 promoter region and 5′ UTR were inversely correlated with antioxidant indicators and protein oxidation markers (ρ: −0.45 to −0.75, p < 0.05) in fetal neural tissues, respectively. In a whole-embryo cultured mouse model, hypomethylation of the Zic4 promoter region and 5′ UTR and upregulation of Zic4 were observed, coupled with increased NTD rates after BaP exposure. The antioxidant N-acetyl-L-cysteine normalized the changes observed in the BaP exposure group.ConclusionHypomethylation of the ZIC4 promoter region and 5′ UTR may increase the risk for NTDs; oxidative stress is likely to play a role in the methylation change of Zic4 in response to PAH exposure in NTD formation.

Background: Cerebellar degeneration as a consequence of a malignancy is a rare condition most commonly related to the presence of anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. In recent years, several reports have indicated Zinc-finger protein 4 (Zic4) antibodies being associated with paraneoplastic cerebellar degeneration (PCD) in patients with small cell lung carcinoma. However, the prevalence and the significance of Zic4-antibodies may be underestimated due to their co-occurrence with more frequent antibodies such as anti-Hu. A literature review of isolated Zic4 mediated paraneoplastic syndromes yielded 14 cases reporting mainly benign clinical courses when treated early.Case Presentation: We present the case of a 67-year-old woman with progressive Zic4 antibody mediated PCD and rhombencephalitis. Immunomodulatory treatment, including intravenous methylprednisolone, plasmaphereses, and intravenous immunoglobulin (IVIG) was administered. Small cell lung cancer (SCLC) was detected, lobectomy performed and cyclophosphamide started. Despite this considerable therapeutic effort, rhombencephalitis led to defiant dysautonomia.Conclusion: Paraneoplastic syndromes related to isolated Zic4 antibodies are rare and typically show a benign clinical course. Here, we present the first case of a rapidly progressive isolated Zic4 associated PCD and rhombencephalitis. Despite considerable therapeutic efforts, the patient passed away on autonomic dysfunction, highlighting the significance of Zic4 associated disease. [ABSTRACT FROM AUTHOR]

Objectives: Aberrations in Wnt and Shh signaling pathways are related to the pathogenesis of head and neck carcinomas, and their activation frequently results from epigenetic alterations. This study aimed to assess the frequency of methylation of negative regulators of Wnt signaling: CXXC4, DACT2, HDPR1, and FBXW11 and Shh signaling: HHIP, PTCH1, SUFU, ZIC1, and ZIC4 and correlate it with clinicopathological features in this group of patients. Materials and methods: Methylation-specific PCR was used to detect gene promoter methylation, and real-time PCR was used to assess gene expression level. Results: The analysis of the occurrence of gene promoter methylation in head and neck carcinoma cell lines indicated that CXXC4, DACT2, HHIP, ZIC1, and ZIC4 are methylated in these tumors. These genes were further analyzed in tumor sections from oral and laryngeal cancer patients. Gene methylation rate was higher in laryngeal tumors. The methylation index in tumor samples correlated with the overall survival in a subgroup of oral cancer patients who died of the disease. Moreover, ZIC4 methylation correlated with lymph node involvement in oral cancer patients. Conclusions: Our findings corroborate that the activation of Wnt signaling in head and neck squamous cell carcinoma (HNSCC) is related to epigenetic silencing of its negative regulators. Moreover, the results indicate that the same mechanism of activation may operate in the case of Shh signaling. Clinical relevance: The methylation of ZIC4 may be considered a new prognostic marker in oral cavity and oropharyngeal tumors. Further investigations should determine the diagnostic significance of methylation of ZIC4, HHIP, and DACT2 in head and neck carcinomas. [ABSTRACT FROM AUTHOR]

We report on a patient with a 6.5 Mb interstitial de novo deletion in 3q24q25.2, characterized by array CGH. The patient is a 4-year and 2-month-old girl, who presented to us with mild developmental delay, absence of language, facial dysmorphism, hirsutism, strabismus, and Dandy-Walker Malformation. The main clinical signs typical of WS (Wisconsin syndrome) are evident in the patient. The molecular mapping of WS in 3q23q25 allowed geneticists to define the syndrome more accurately. Comparing the present patient's phenotype with that of cases with a molecular characterization so far reported, it was possible to narrow the critical region for WS to an interval of 750 Kb, where two genes ( MBNL1 and TMEM14E) are harbored. The potential role of MBNL1 in causing the WS phenotype is discussed. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Murine Zic genes ( Zic1-5) are expressed in the dorsal hindbrain and in periotic mesenchyme (POM) adjacent to the developing inner ear. Zic genes are involved in developmental signaling pathways in many organ systems, including the ear, although their exact roles haven't been fully elucidated. This report examines the role of Zic1, Zic2, and Zic4 during inner ear development in mouse mutants in which these Zic genes are affected. Results: Zic1/ Zic4 double mutants don't exhibit any apparent defects in inner ear morphology. By contrast, inner ears from Zic2kd/kd and Zic2Ku/Ku mutants have severe but variable morphological defects in endolymphatic duct/sac and semicircular canal formation and in cochlear extension in the inner ear. Analysis of otocyst patterning in the Zic2Ku/Ku mutants by in situ hybridization showed changes in the expression patterns of Gbx2 and Pax2. Conclusions: The experiments provide the first genetic evidence that the Zic genes are required for morphogenesis of the inner ear. Zic2 loss-of-function doesn't prevent initial otocyst patterning but leads to molecular abnormalities concomitant with morphogenesis of the endolymphatic duct. Functional hearing deficits often accompany inner ear dysmorphologies, making Zic2 a novel candidate gene for ongoing efforts to identify the genetic basis of human hearing loss. Developmental Dynamics 243:1487-1498, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We report a case carrying a de novo interstitial deletion of chromosome 3q22-q25. The clinical phenotype of this case included blepharophimosis/ptosis/epicanthus inversus syndrome, Dandy-Walker malformation, and global developmental delay. Contiguous heterozygous deletion of FOXL2, ATR, ZIC1, and ZIC4 was postulated as the causative mechanism of the clinical phenotype. The association of blepharophimosis, ptosis, and epicanthus inversus syndrome with developmental delay or mental retardation may be an indication for the use of brain imaging and chromosomal analysis capable of detecting chromosomal rearrangements encompassing several candidate genes. [ABSTRACT FROM PUBLISHER]

Dandy–Walker syndrome (DWS) is a brain malformation of unknown etiology, but several reports have been published indicating that there is a causal relationship to various types of chromosomal abnormalities and malformation syndromes. In the present article, we present a bibliographical survey of several previously issued reports on chromosomal abnormalities associated with DWS, including our case of DWS found in trisomy 18. There are various types of chromosomal abnormalities associated with DWS; most of them are reported in chromosome 3, 9, 13 and 18. We also summarize some other chromosomal abnormalities and various congenital malformation syndromes. [ABSTRACT FROM AUTHOR]

Medaka is one of the prominent model animals, which also include other fishes such as Fugu and zebrafish. Its genome is relatively compact but has not been well characterized. Here we have sequenced a 229-kb region of medaka, containing the Double anal fin (Da) locus, and compared its structure to those in Fugu, human, and mouse. This region, representing a gene-poor region, contains no major rearrangements and can be readily compared among different species. Comparison of G+C contents and repeats suggested that medaka and Fugu are highly related as expected and that medaka is more similar to mammals than Fugu is. Sequence comparisons of developmental genes zic1 and zic4, identified within this region, revealed that zic1, but not zic4, is highly conserved among vertebrates. The 5′ coding region of zic4 is, however, extremely homologous among fishes with little synonymous substitutions, implying its distinct function in fish. [Copyright &y& Elsevier]

We report three cases of vermian cerebellar hypermetabolism in patients with autoimmune encephalitis. One of our patients was positive for anti-Ma2 antibodies and one for anti-Zic4 antibodies while the remaining patient did not present any known antibodies. The seronegative patient deteriorated after immune checkpoint inhibitor treatment for a pulmonary adenocarcinoma and improved with immunosuppressive drugs, which is in favour of an underlying autoimmune mechanism. They all presented with subacute neurological symptoms. Brain magnetic resonance imaging was normal except in one patient, where hyperintensities were present on FLAIR sequence around the third ventricle and the cerebral aqueduct. 18 F-FDG brain positron emission tomography with computed tomography ( 18 F-FDG PET-CT) demonstrated an unusual vermian cerebellar hypermetabolism in the three cases. While cerebellar hypermetabolism on 18 F-FDG PET-CT has been described in various neurological diseases, such vermian - and more broadly cerebellar - hypermetabolism was seldom described in previous studies on autoimmune encephalitis. When differential diagnoses have been ruled out, this pattern may be of interest for the positive diagnosis of autoimmune encephalitis in difficult diagnostic cases., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Stiff person spectrum disorders (SPSD) are a broad group of immune-mediated disorders. Clinical presentations include classical stiff person syndrome (SPS), focal SPS, and progressive encephalomyelitis with rigidity and myoclonus (PERM). The most frequently associated antibodies are anti-GAD65, anti-GlyR, anti-amphiphysin, and anti-DPPX. Immunotherapy is the primary treatment modality. We present an illustrative case series of three patients: anti-GlyR antibody-mediated PERM presenting as rapidly progressive dementia; anti-amphiphysin antibody-mediated SPS; and SPS presentation with anti-Zic4 antibodies, spasmodic laryngeal stridor and fluctuating eyelid ptosis. Clinical characteristics, CSF findings, neurophysiological features, adequate immunological assays and a high suspicion index are essential for prompt diagnosis and management. Unlabelled Image • Stiff person spectrum disorders (SPSD) are uncommon immune-mediated conditions. • The extent of SPSD phenotypic and antibody heterogeneity is not fully known. • We report anti-GlyR, anti-amphiphysin, and anti-Zic4 antibody-mediated SPSD cases. • This is the first report of anti-Zic4 antibody-mediated SPSD. • High index of suspicion is essential for prompt diagnosis of SPSD. [ABSTRACT FROM AUTHOR]