A novel ZC4H2 gene mutation, K209N, in Japanese siblings with arthrogryposis multiplex congenita and intellectual disability: characterization of the K209N mutation and clinical findings

Kondo, Daisuke; Noguchi, Atsuko; Takahashi, Ikuko; Kubota, Hirokazu; Yano, Tamami; Sato, Yoko; Toyono, Miyuki; Sawaishi, Yukio; Takahashi, Tsutomu

doi:10.1016/j.braindev.2018.05.003

Cited by 14 publications

(17 citation statements)

References 17 publications

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“…Detailed clinical descriptions are presented in Supporting Information Results. In the clinical evaluation, we also included publicly accessible information of three females reported to DECIPHER and all families and simplex cases published to date (Godfrey et al, ; Hirata et al, ; Kondo et al, ; May et al, ; Okubo et al, ; Zanzottera et al, ). A compilation of the main ( ≥ 30%) clinical features of affected males and females from these 42 families is given in Table and of the additional less common clinical features (< 30%) in Table S2.…”

Section: Resultsmentioning

confidence: 99%

Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

et al. 2019

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Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/ or (neurogenic) AMC. K E Y W O R D S fetal hypo-/akinesia, club foot/-feet, complicated spastic paraplegia/ spasticity, Xq11.2 microdeletion, ZC4H2, ZC4H2-Associated Rare Disorders (ZARD) DDD study presents independent

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Section: Resultsmentioning

confidence: 99%

Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

et al. 2019

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“…However, female patients show various symptoms especially in deletion and nonsense mutation cases, and some of them are considered to be associated with nonrandom X-chromosome inactivation (XCI) (Hirata et al, 2013). So far, 7 missense mutations, 1 nonsense mutation, 1 frameshift mutation, 1 chromosomal breakpoint in Xq11.2, and 4 deletions in ZC4H2 gene have been reported ( Figure 1) (Godfrey, Dowlatshahi, Martin, & Rothkopf, 2018;Hennekam, Barth, Van Lookeren Campagne, De Visser, & Dingemans, 1991;Hirata et al, 2013;Kondo et al, 2018;May et al, 2015;Okubo et al, 2018;Zanzottera et al, 2017). The clinical presentation and genetic changes in female patients have been summarized in Table 1.…”

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confidence: 99%

A novel de novo nonsense mutation in ZC4H2 causes Wieacker‐Wolff Syndrome

Wang

Guo

et al. 2019

Molec Gen & Gen Med

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Background Wieacker‐Wolff syndrome (WWS) is a congenital X‐linked neuromuscular disorder, which was firstly reported in 1985. Zinc finger C4H2‐type containing (ZC4H2) gene has been found to be associated with the disease pathogenesis. However, the underlying mechanism remains elusive. Methods Whole‐exome sequencing was performed to identify the mutations. Expression plasmids were constructed and cell culture and immune‐biochemical assays were used to examine the effects of the mutation. Results We reported a female patient with classical symptoms of WWS and discovered a novel nonsense heterozygous mutation (p.R67X; c.199C>T) in ZC4H2 gene in the patient but not in her parents. The mutation resulted in a 66 amino‐acid truncated ZC4H2 protein. The mutation is located in the key helix domain and it altered the subcellular locations of the mutant ZC4H2 protein. X‐chromosome inactivation (XCI) pattern analysis revealed that the XCI ratio of the proband was 22:78. Conclusion Female heterozygous carriers with nonsense mutation with a truncated ZC4H2 protein could lead to the pathogenesis of Wieacker‐Wolff syndrome and our study provides a potential new target for the disease treatment.

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“…Expression is predominately found in the brain and spinal cord in the embryonic stage [20]. ZC4H2 also contains a nuclear localization signal, and shuttles between the nucleus and the cytosol [20,35]. ZC4H2 has been shown to interact with Smad signaling proteins [23] and with the ubiquitin E3 ligase Rnf220 [22,36], and disease causing mutations may influence the transcriptional regulation of specific genes by these targets, thereby affecting neuronal development.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, although zinc-finger-containing proteins are best known in the context of transcription in the nucleus, it is not uncommon that they affect protein function via direct interaction [37]. Notably, many disease-causing mutations in the ZC4H2 gene affect the nuclear localization signal, leading to a more abundant presence in the cytosol [35,38]. It will be of great interest to further investigate whether such cytosolic mutants are more prone to enhance TRPV4 function, and thereby provoke disease symptoms that are common to TRPV4-pathies and ZARDs.…”

Section: Discussionmentioning

confidence: 99%

The Zinc-Finger Domain Containing Protein ZC4H2 Interacts with TRPV4, Enhancing Channel Activity and Turnover at the Plasma Membrane

Vangeel

Janssens

Lemmens

et al. 2020

IJMS

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The Ca2+-permeable Transient Receptor Potential channel vanilloid subfamily member 4 (TRPV4) is involved in a broad range of physiological processes, including the regulation of systemic osmotic pressure, bone resorption, vascular tone, and bladder function. Mutations in the TRPV4 gene are the cause of a spectrum of inherited diseases (or TRPV4-pathies), which include skeletal dysplasias, arthropathies, and neuropathies. There is little understanding of the pathophysiological mechanisms underlying these variable disease phenotypes, but it has been hypothesized that disease-causing mutations affect interaction with regulatory proteins. Here, we performed a mammalian protein–protein interaction trap (MAPPIT) screen to identify proteins that interact with the cytosolic N terminus of human TRPV4, a region containing the majority of disease-causing mutations. We discovered the zinc-finger domain-containing protein ZC4H2 as a TRPV4-interacting protein. In heterologous expression experiments, we found that ZC4H2 increases both the basal activity of human TRPV4 as well as Ca2+ responses evoked by ligands or hypotonic cell swelling. Using total internal reflection fluorescence (TIRF) microscopy, we further showed that ZC4H2 accelerates TRPV4 turnover at the plasma membrane. Overall, these data demonstrate that ZC4H2 is a positive modulator of TRPV4, and suggest a link between TRPV4 and ZC4H2-associated rare disorders, which have several neuromuscular symptoms in common with TRPV4-pathies.

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A novel ZC4H2 gene mutation, K209N, in Japanese siblings with arthrogryposis multiplex congenita and intellectual disability: characterization of the K209N mutation and clinical findings

Cited by 14 publications

References 17 publications

Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

A novel de novo nonsense mutation in ZC4H2 causes Wieacker‐Wolff Syndrome

The Zinc-Finger Domain Containing Protein ZC4H2 Interacts with TRPV4, Enhancing Channel Activity and Turnover at the Plasma Membrane

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