ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability

Motor Neural Circuit Laboratory • Hirata Group

Mutations of ZC4H2 are associated with arthrogryposis multiplex congenita and intellectual disability and through impairment of central and peripheral synaptic plasticity
Hirata, H.*, Nanda, I.*, van Riesen, A.*, McMichael, G.*, Hu, H.*, Hambrock, M., Papon, M.-A., Fischer, U., Marouillat, S., Ding, C., Alirol, S., Bienek, M., Preisler-Adams, S., Grimme, A., Seelow, D., Webster, R., Haan, E., MacLennan, A., Stenzel, W., Yap, T. Y., Gardner, A., Nguyen, L. S., Shaw, M., Lebrun, N., Haas, S. A., Kress, W., Haaf, T., Schellenberger, E., Chelly, J., Viot, G., Shaffer, L. G., Rosenfeld, J. A., Kramer, N., Falk, R., El-Khechen, D., Escobar, L. F., Hennekam, R., Wieacker, P., Hübner, C., Ropers, H.-H., Gecz, J., Schuelke, M., Laumonnier, F. and Kalscheuer, V. M. (*Equal contribution)
American Journal of Human Genetics 92: 681-695 (2013). doi: 10.1016/j.bbr.2011.03.031

Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. In this study, we identified disease-causing mutations in the zinc-finger gene ZC4H2 in an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired primary motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 defects cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems. Our results highlight the importance of ZC4H2 for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.

This is a collaborative work with Dr. Vera M. Kalscheuer (Max Planck Institute for Molecular Genetics), Dr. Markus Schuelke (Charité Universitätsmedizin Berlin) and other researchers and is supported by the NIG Collaborative Research.

In zebrafish embryos, zc4h2 is expressed by forebrain, midbrain, hindbrain and spinal cord.

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