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

Hirata, H., Nanda, I., van Riesen, A., McMichael, G., Hu, H., Hambrock, M., et al. (2013). ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity. The American Journal of Human Genetics, 92(5), 681-695. doi:10.1016/j.ajhg.2013.03.021.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0018-C63A-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0018-C646-F
Genre: Journal Article

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 Creators:
Hirata, H., Author
Nanda, I., Author
van Riesen, A., Author
McMichael, G., Author
Hu, H., Author
Hambrock, M., Author
Papon, M. A., Author
Fischer, U., Author
Marouillat, S., Author
Ding, C., Author
Alirol, S., Author
Bienek, M., Author
Preisler-Adams, S., Author
Grimme, A., Author
Seelow, D., Author
Webster, R., Author
Haan, E., Author
MacLennan, A., Author
Stenzel, W., Author
Yap, T. Y., Author
Gardner, A., AuthorNguyen, L. S., AuthorShaw, M., AuthorLebrun, N., AuthorHaas, S. A.1, Author              Kress, W., AuthorHaaf, T., AuthorSchellenberger, E., AuthorChelly, J., AuthorViot, G., AuthorShaffer, L. G., AuthorRosenfeld, J. A., AuthorKramer, N., AuthorFalk, R., AuthorEl-Khechen, D., AuthorEscobar, L. F., AuthorHennekam, R., AuthorWieacker, P., AuthorHubner, C., AuthorRopers, H. H.2, Author              Gecz, J., AuthorSchuelke, M., AuthorLaumonnier, F., AuthorKalscheuer, V. M.3, Author               more..
Affiliations:
1Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 73, 14195 Berlin, Germany, ou_1479640              
2Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr, 73, 14195 Berlin, Germany, ou_1433549              
3Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr, 73, 14195 Berlin, Germany, ou_1479642              

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Free keywords: Abnormalities, Multiple/*genetics/pathology Animals Arthrogryposis/*genetics/pathology Carrier Proteins/*genetics Cells, Cultured Chromosome Breakpoints Comparative Genomic Hybridization Female Genetic Predisposition to Disease/*genetics Haplotypes/genetics High-Throughput Nucleotide Sequencing Humans Immunoblotting In Situ Hybridization Intellectual Disability/*genetics/pathology Male Mice Mutation/genetics Neuronal Plasticity/*genetics Pedigree Synapses/genetics Zebrafish Zinc Fingers/*genetics
 Abstract: 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 alpha-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.

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Language(s): eng - English
 Dates: 2013-04-252013-05-02
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.ajhg.2013.03.021
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
URI: http://www.ncbi.nlm.nih.gov/pubmed/23623388
 Degree: -

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Title: The American Journal of Human Genetics
  Abbreviation : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 92 (5) Sequence Number: - Start / End Page: 681 - 695 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1