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.

• Authors: Dan Wang, Dongjie Hu, Zhichao Guo, Rong Hu, Qunxian Wang, Yannan Liu, Mingjing Liu, Zijun Meng, Huan Yang, Yun Zhang, Fang Cai, Weihui Zhou, Weihong Song
• Journal: Molecular genetics & genomic medicine (Mol Genet Genomic Med) Vol. 8 Issue 2 Pg. e1100 (02 2020) ISSN: 2324-9269 [Electronic] United States
• PMID: 31885220 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Chemical References

• Codon, Nonsense
• Intracellular Signaling Peptides and Proteins
• Nuclear Proteins
• ZC4H2 protein, human

Topics

• Apraxias (genetics, pathology)
• Codon, Nonsense
• Contracture (genetics, pathology)
• Female
• Genetic Diseases, X-Linked (genetics, pathology)
• HEK293 Cells
• Humans
• Infant
• Intracellular Signaling Peptides and Proteins (chemistry, genetics, metabolism)
• Muscular Atrophy (genetics, pathology)
• Nuclear Proteins (chemistry, genetics, metabolism)
• Ophthalmoplegia (genetics, pathology)
• Protein Domains
• X Chromosome Inactivation