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Hum Mol Genet. 2015 Sep 1;24(17):4848-61. doi: 10.1093/hmg/ddv208. Epub 2015 Jun 8.

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

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Greenwood Genetic Center, Greenwood, SC 29646, USA.
Department of Biology, Chungnam National University, Daejeon 305-764, Korea.
Department of Child Health, University of Missouri School of Medicine, Columbia, MO 65212, USA.
Division of Genetics and Metabolism, University of Florida College of Medicine, Gainesville, FL 33612, USA.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
Arkansas Children's Hospital, Little Rock, AR 72202, USA.
Institute of Medical Genetics, Catholic University, Rome 00-168, Italy.
Institute of Medical Genetics, University of Zurich, Schwerzenbach 8006, Switzerland.
Department of Bioinformatics, Erasmus University Medical Center, Rotterdam 3015, Netherlands.
Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA.
Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK and.
Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA.
Greenwood Genetic Center, Greenwood, SC 29646, USA,
Department of Biology, Chungnam National University, Daejeon 305-764, Korea,


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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