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

Abstract

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.

Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

“…On the MRI findings, notably, in our patient, they were consistent with those described both in the case by Zanzottera et al ( 21 )—thin brainstem and corpus callosum—and by Wang et al ( 22 )—slight ventricular enlargement and diffuse cerebral atrophy.…”

“…Importantly, despite the fact that WWS is an X-linked recessive disorder, females carrying heterozygous ZC4H2 mutations may display a mild intellectual disability phenotype as well as subtle distal contractures and sometimes clubfoot ( 21 , 25 ). A recent study by Wang et al ( 22 ) demonstrated that mechanisms underlying X-chromosome inactivation (XCI) in females are not necessarily implicated in the disease phenotype. In this regard, XCI seems to be correlated with a milder phenotype in female carriers ( 22 ).…”

“…A recent study by Wang et al ( 22 ) demonstrated that mechanisms underlying X-chromosome inactivation (XCI) in females are not necessarily implicated in the disease phenotype. In this regard, XCI seems to be correlated with a milder phenotype in female carriers ( 22 ).…”

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

“…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.…”

The many faces of the E3 ubiquitin ligase, RNF220, in neural development and beyond

“…(b) In IFN-STAT1 signaling, K63-linked polyubiquitination of STAT1 at K110 by RNF220 promotes its interaction with JAK1 and its subsequent activation. RNF220 is also a target of STAT1 signaling (Guo et al, 2021) TA B L E 1 RNF220/ZC4H2 mutations or misregulation in human diseases Hirata et al, 2013;May et al, 2015;Nagara et al, 2020;Wang et al, 2020). AMCs are genetically heterogeneous and include various conditions affecting the formation or function of neuromuscular junctions (NMJs), skeletal muscles and bones, and the nervous system (Ma & Yu, 2017).…”