ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity

Hiromi Hirata, Indrajit Nanda, Anne Van Riesen, Gai McMichael, Hao Hu, Melanie Hambrock, Marie Amélie Papon, Ute Fischer, Sylviane Marouillat, Can Ding, Servane Alirol, Melanie Bienek, Sabine Preisler-Adams, Astrid Grimme, Dominik Seelow, Richard Webster, Eric Haan, Alastair MacLennan, Werner Stenzel, Tzu Ying YapAlison Gardner, Lam Son Nguyen, Marie Shaw, Nicolas Lebrun, Stefan A. Haas, Wolfram Kress, Thomas Haaf, Elke Schellenberger, Jamel Chelly, Géraldine Viot, Lisa G. Shaffer, Jill A. Rosenfeld, Nancy Kramer, Rena Falk, Dima El-Khechen, Luis F. Escobar, Raoul Hennekam, Peter Wieacker, Christoph Hübner, Hans Hilger Ropers, Jozef Gecz, Markus Schuelke, Frédéric Laumonnier, Vera M. Kalscheuer

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37 Citations (Scopus)


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. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. 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.

Original languageEnglish
Pages (from-to)681-695
Number of pages15
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 2 May 2013
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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