title: ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
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.
authors.affiliation: Center for Frontier Research, National Institute of Genetics, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Mishima 411-8540, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hirata
authors.forename: Indrajit
authors.initials: I
authors.lastname: Nanda
authors.forename: Anne
authors.initials: A
authors.lastname: van Riesen
authors.forename: Gai
authors.initials: G
authors.lastname: McMichael
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Melanie
authors.initials: M
authors.lastname: Hambrock
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Papon
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
authors.forename: Sylviane
authors.initials: S
authors.lastname: Marouillat
authors.forename: Can
authors.initials: C
authors.lastname: Ding
authors.forename: Servane
authors.initials: S
authors.lastname: Alirol
authors.forename: Melanie
authors.initials: M
authors.lastname: Bienek
authors.forename: Sabine
authors.initials: S
authors.lastname: Preisler-Adams
authors.forename: Astrid
authors.initials: A
authors.lastname: Grimme
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.forename: Richard
authors.initials: R
authors.lastname: Webster
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.forename: Alastair
authors.initials: A
authors.lastname: MacLennan
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.forename: Tzu Ying
authors.initials: TY
authors.lastname: Yap
authors.forename: Alison
authors.initials: A
authors.lastname: Gardner
authors.forename: Lam Son
authors.initials: LS
authors.lastname: Nguyen
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebrun
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.forename: Elke
authors.initials: E
authors.lastname: Schellenberger
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Géraldine
authors.initials: G
authors.lastname: Viot
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Nancy
authors.initials: N
authors.lastname: Kramer
authors.forename: Rena
authors.initials: R
authors.lastname: Falk
authors.forename: Dima
authors.initials: D
authors.lastname: El-Khechen
authors.forename: Luis F
authors.initials: LF
authors.lastname: Escobar
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Peter
authors.initials: P
authors.lastname: Wieacker
authors.forename: Christoph
authors.initials: C
authors.lastname: Hübner
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
authors.forename: Frédéric
authors.initials: F
authors.lastname: Laumonnier
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D056905:Chromosome Breakpoints; D055028:Comparative Genomic Hybridization; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics*; D009687:Nuclear Proteins; D010375:Pedigree; D013569:Synapses / Q000235:genetics; D015027:Zebrafish; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C582075:ZC4H2 protein, human