Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the <i>ZC4H2</i> Gene
Pathogenic variants of zinc finger C4H2-type containing (<i>ZC4H2</i>) on the X chromosome cause a group of genetic diseases termed ZC4H2-associated rare disorders (ZARD), including Wieacker-Wolff Syndrome (WRWF) and Female-restricted Wieacker-Wolff Syndrome (WRWFFR). In the current stud...
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MDPI AG
2022-08-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/9/1558 |
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| author | Jing-Jing Sun Qin Cai Miao Xu Yan-Na Liu Wan-Rui Li Juan Li Li Ma Cheng Cai Xiao-Hui Gong Yi-Tao Zeng Zhao-Rui Ren Fanyi Zeng |
| author_facet | Jing-Jing Sun Qin Cai Miao Xu Yan-Na Liu Wan-Rui Li Juan Li Li Ma Cheng Cai Xiao-Hui Gong Yi-Tao Zeng Zhao-Rui Ren Fanyi Zeng |
| author_sort | Jing-Jing Sun |
| collection | DOAJ |
| description | Pathogenic variants of zinc finger C4H2-type containing (<i>ZC4H2</i>) on the X chromosome cause a group of genetic diseases termed ZC4H2-associated rare disorders (ZARD), including Wieacker-Wolff Syndrome (WRWF) and Female-restricted Wieacker-Wolff Syndrome (WRWFFR). In the current study, a de novo c.352C>T (p.Gln118*) mutation in <i>ZC4H2</i> (NM_018684.4) was identified in a female neonate born with severe arthrogryposis multiplex congenita (AMC) and Pierre-Robin sequence (cleft palate and micrognathia). Plasmids containing the wild-type (WT), mutant-type (MT) <i>ZC4H2,</i> or <i>GFP</i> report gene (N) were transfected in 293T cell lines, respectively. RT-qPCR and western blot analysis showed that ZC4H2 protein could not be detected in the 293T cells transfected with MT <i>ZC4H2</i>. The RNA seq results revealed that the expression profile of the MT group was similar to that of the N group but differed significantly from the WT group, indicating that the c.352C>T mutation resulted in the loss of function of ZC4H2. Differentially expressed genes (DEGs) enrichment analysis showed that c.352C>T mutation inhibited the expression levels of a series of genes involved in the oxidative phosphorylation pathway. Subsequently, expression levels of <i>ZC4H2</i> were knocked down in neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) by lentiviral-expressed small hairpin RNAs (shRNAs) against <i>ZC4H2</i>. The results also demonstrated that decreasing the expression of <i>ZC4H2</i> significantly reduced the growth of NSCs by affecting the expression of genes related to the oxidative phosphorylation signaling pathway. Taken together, our results strongly suggest that <i>ZC4H2</i> c.352C>T (p.Gln118*) mutation resulted in the loss of protein function and caused WRWFFR. |
| first_indexed | 2024-03-09T23:56:05Z |
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| id | doaj.art-07d12bcadc314e8998db5434987363f2 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T23:56:05Z |
| publishDate | 2022-08-01 |
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| series | Genes |
| spelling | doaj.art-07d12bcadc314e8998db5434987363f22023-11-23T16:24:08ZengMDPI AGGenes2073-44252022-08-01139155810.3390/genes13091558Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the <i>ZC4H2</i> GeneJing-Jing Sun0Qin Cai1Miao Xu2Yan-Na Liu3Wan-Rui Li4Juan Li5Li Ma6Cheng Cai7Xiao-Hui Gong8Yi-Tao Zeng9Zhao-Rui Ren10Fanyi Zeng11Shanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaShanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaShanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaShanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaShanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaDepartment of Neonatology, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, ChinaDepartment of Neonatology, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, ChinaDepartment of Neonatology, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, ChinaDepartment of Neonatology, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, ChinaShanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaShanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaShanghai Institute of Medical Genetics, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, ChinaPathogenic variants of zinc finger C4H2-type containing (<i>ZC4H2</i>) on the X chromosome cause a group of genetic diseases termed ZC4H2-associated rare disorders (ZARD), including Wieacker-Wolff Syndrome (WRWF) and Female-restricted Wieacker-Wolff Syndrome (WRWFFR). In the current study, a de novo c.352C>T (p.Gln118*) mutation in <i>ZC4H2</i> (NM_018684.4) was identified in a female neonate born with severe arthrogryposis multiplex congenita (AMC) and Pierre-Robin sequence (cleft palate and micrognathia). Plasmids containing the wild-type (WT), mutant-type (MT) <i>ZC4H2,</i> or <i>GFP</i> report gene (N) were transfected in 293T cell lines, respectively. RT-qPCR and western blot analysis showed that ZC4H2 protein could not be detected in the 293T cells transfected with MT <i>ZC4H2</i>. The RNA seq results revealed that the expression profile of the MT group was similar to that of the N group but differed significantly from the WT group, indicating that the c.352C>T mutation resulted in the loss of function of ZC4H2. Differentially expressed genes (DEGs) enrichment analysis showed that c.352C>T mutation inhibited the expression levels of a series of genes involved in the oxidative phosphorylation pathway. Subsequently, expression levels of <i>ZC4H2</i> were knocked down in neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) by lentiviral-expressed small hairpin RNAs (shRNAs) against <i>ZC4H2</i>. The results also demonstrated that decreasing the expression of <i>ZC4H2</i> significantly reduced the growth of NSCs by affecting the expression of genes related to the oxidative phosphorylation signaling pathway. Taken together, our results strongly suggest that <i>ZC4H2</i> c.352C>T (p.Gln118*) mutation resulted in the loss of protein function and caused WRWFFR.https://www.mdpi.com/2073-4425/13/9/1558WRWFWRWFFRZC4H2nonsense mutation |
| spellingShingle | Jing-Jing Sun Qin Cai Miao Xu Yan-Na Liu Wan-Rui Li Juan Li Li Ma Cheng Cai Xiao-Hui Gong Yi-Tao Zeng Zhao-Rui Ren Fanyi Zeng Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the <i>ZC4H2</i> Gene Genes WRWF WRWFFR ZC4H2 nonsense mutation |
| title | Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the <i>ZC4H2</i> Gene |
| title_full | Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the <i>ZC4H2</i> Gene |
| title_fullStr | Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the <i>ZC4H2</i> Gene |
| title_full_unstemmed | Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the <i>ZC4H2</i> Gene |
| title_short | Loss of Protein Function Causing Severe Phenotypes of Female-Restricted Wieacker Wolff Syndrome due to a Novel Nonsense Mutation in the <i>ZC4H2</i> Gene |
| title_sort | loss of protein function causing severe phenotypes of female restricted wieacker wolff syndrome due to a novel nonsense mutation in the i zc4h2 i gene |
| topic | WRWF WRWFFR ZC4H2 nonsense mutation |
| url | https://www.mdpi.com/2073-4425/13/9/1558 |
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