ArticleHuman molecular genetics2015
ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 58 citations in OpenAlex.
- The pathogenic factor of ZC4H2-associated rare disorder is a postsynaptic regulator for synaptic activity and cognitive function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Case Report: A novel missense variant inFrontiers in pediatrics · 2025Article
- Wieacker-Wolff syndrome with hyperinsulinemic hypoglycemia successfully treated using diazoxide: A case report.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2025Article
- RFC2 may contribute to the pathogenicity of Williams syndrome revealed in a zebrafish model.Journal of genetics and genomics = Yi chuan xue bao · 2024Article
- SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.Annals of neurology · 2024Article
- Genotype-Phenotype Correlations and Sex Differences in ZC4H2-Associated Rare Disorder.Pediatric neurology · 2024Article
- Loss ofGenes · 2024Article
- PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.EMBO reports · 2024Article
- Impairments of cerebellar structure and function in a zebrafish KO of neuropsychiatric risk gene znf536.Translational psychiatry · 2024Article
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
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- Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression.Journal of molecular cell biology · 2022Article
- Disease Modeling of Rare Neurological Disorders in Zebrafish.International journal of molecular sciences · 2022Review
- Clinical findings and a DNA methylation signature in kindreds with alterations in ZNF711.European journal of human genetics : EJHG · 2022Article
- A 7-year old female with arthrogryposis multiplex congenita, Duane retraction syndrome, and Marcus Gunn phenomenon due to a ZC4H2 gene mutation: a clinical presentation of the Wieacker-Wolff syndrome.Ophthalmic genetics · 2021Article
- Wieacker-Wolff syndrome, a distinctive phenotype of arthrogryposis multiplex congenita caused by a "de novo"Clinical case reports · 2021Article
- A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.Genes · 2021Article
- Zebrafish as an animal model for biomedical research.Experimental & molecular medicine · 2021Review
- Neuromuscular and Neuroendocrinological Features Associated WithFrontiers in neurology · 2021Article
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Authors and funding
25 authors at 11 institutions in 5 countries.
Funding
Abstract
Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID re-sequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specific markers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injected with human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity of many brain and spinal circuits.
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