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ZC4H2 Mutations Are Associated with Arthrogryposis Multiplex Congenita and Intellectual Disability through Impairment of Central and Peripheral Synaptic Plasticity

Overview of attention for article published in American Journal of Human Genetics, April 2013
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Title
ZC4H2 Mutations Are Associated with Arthrogryposis Multiplex Congenita and Intellectual Disability through Impairment of Central and Peripheral Synaptic Plasticity
Published in
American Journal of Human Genetics, April 2013
DOI 10.1016/j.ajhg.2013.03.021
Pubmed ID
Authors

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 Yap, Alison 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, Hirata H, Nanda I, van Riesen A, McMichael G, Hu H, Hambrock M, Papon MA, 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 TY, Gardner A, Nguyen LS, Shaw M, Lebrun N, Haas SA, Kress W, Haaf T, Schellenberger E, Chelly J, Viot G, Shaffer LG, Rosenfeld JA, Kramer N, Falk R, El-Khechen D, Escobar LF, Hennekam R, Wieacker P, Hübner C, Ropers HH, Gecz J, Schuelke M, Laumonnier F, Kalscheuer VM

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 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.

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The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 63 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
Argentina 1 2%
Unknown 61 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 16 25%
Student > Master 14 22%
Researcher 12 19%
Other 5 8%
Professor 4 6%
Other 12 19%
Readers by discipline Count As %
Medicine and Dentistry 22 35%
Agricultural and Biological Sciences 15 24%
Unspecified 6 10%
Biochemistry, Genetics and Molecular Biology 6 10%
Neuroscience 4 6%
Other 10 16%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 May 2013.
All research outputs
#2,670,460
of 5,037,615 outputs
Outputs from American Journal of Human Genetics
#2,567
of 2,988 outputs
Outputs of similar age
#46,181
of 92,789 outputs
Outputs of similar age from American Journal of Human Genetics
#45
of 48 outputs
Altmetric has tracked 5,037,615 research outputs across all sources so far. This one is in the 33rd percentile – i.e., 33% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,988 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 9.2. This one is in the 6th percentile – i.e., 6% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 92,789 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 37th percentile – i.e., 37% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 48 others from the same source and published within six weeks on either side of this one. This one is in the 6th percentile – i.e., 6% of its contemporaries scored the same or lower than it.