ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Melanie May, Kyu Seok Hwang, Judith Miles, Charlie Williams, Tejasvi Niranjan, Stephen G. Kahler, Pietro Chiurazzi, Katharina Steindl, Peter J. Van Der Spek, Sigrid Swagemakers, Jennifer Mueller, Shannon Stefl, Emil Alexov, Jeong Im Ryu, Jung Hwa Choi, Hyun Taek Kim, Patrick Tarpey, Giovanni Neri, Lynda Holloway, Cindy SkinnerRoger E. Stevenson, Richard I. Dorsky, Tao Wang, Charles E. Schwartz, Cheol Hee Kim

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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 resequencing 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-specificmarkers 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 injectedwith 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 ofmany brain and spinal circuits.

Original languageEnglish (US)
Pages (from-to)4848-4861
Number of pages14
JournalHuman molecular genetics
Issue number17
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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