1. ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons
- Author
-
Giovanni Neri, Stephen G. Kahler, Katharina Steindl, Jung Hwa Choi, Jennifer Mueller, Peter J. van der Spek, Sigrid M.A. Swagemakers, Kyu Seok Hwang, Charles E. Schwartz, Patrick S. Tarpey, Jeong Im Ryu, Hyun Taek Kim, Cheol-Hee Kim, Melanie May, Richard I. Dorsky, Shannon K. Stefl, Pietro Chiurazzi, Emil Alexov, Judith H. Miles, Lynda Holloway, Cindy Skinner, Roger E. Stevenson, Tao Wang, Tejasvi Niranjan, Charles A. Williams, and Pathology
- Subjects
Central Nervous System ,Male ,Microcephaly ,Interneuron ,Mutant ,Central nervous system ,Gene Expression ,Settore MED/03 - GENETICA MEDICA ,medicine.disease_cause ,Cell Line ,Genes, X-Linked ,Interneurons ,Chlorocebus aethiops ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Zebrafish ,Genetics (clinical) ,Loss function ,Mutation ,biology ,Intracellular Signaling Peptides and Proteins ,Computational Biology ,Nuclear Proteins ,General Medicine ,Articles ,X-Linked ,medicine.disease ,Spinal cord ,biology.organism_classification ,Pedigree ,medicine.anatomical_structure ,Genes ,Organ Specificity ,COS Cells ,Female ,Human medicine ,Carrier Proteins ,Neuroscience - 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.
- Published
- 2015