Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disorders
Abstract Background The calcium/calmodulin‐dependent serine protein kinase gene (CASK) is an essential gene in mammals, critical for neurodevelopment. The purpose of this study is to expand the understanding of the diagnosis of CASK‐linked disorders. Materials/Methods From clinical and genetic mutat...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-11-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.2065 |
| _version_ | 1811233175810080768 |
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| author | Kunfang Yang Longlong Lin Fang Yuan Xiaoguang Li Zhiping Liu Xiaoping Lan Yilin Wang Yun Ren Jiaoyan Li Yucai Chen |
| author_facet | Kunfang Yang Longlong Lin Fang Yuan Xiaoguang Li Zhiping Liu Xiaoping Lan Yilin Wang Yun Ren Jiaoyan Li Yucai Chen |
| author_sort | Kunfang Yang |
| collection | DOAJ |
| description | Abstract Background The calcium/calmodulin‐dependent serine protein kinase gene (CASK) is an essential gene in mammals, critical for neurodevelopment. The purpose of this study is to expand the understanding of the diagnosis of CASK‐linked disorders. Materials/Methods From clinical and genetic mutational analyses, relevant data in 2 Han Chinese patients were collected and analyzed. Real‐time quantitative PCR (RT‐qPCR) was performed to investigate the CASK expression levels in the patients. The X‐chromosome inactivation (XCI) patterns of the patients and their nuclear families were tested by quantitation of methylation of the polymorphic human androgen receptor (HUMARA) locus. Results Two Han Chinese patients both presented with intellectual disability (ID), microcephaly with pontine and cerebellar hypoplasia (MICPCH). Two de novo mutations of c.82C>T (p.Arg28*) and c.846C>G (p.Tyr282*) in CASK have been investigated and predicted to be deleterious, which have produced truncated proteins. The functional protein association network of STRING (http://string‐db.org) generated three‐dimensional (3D) atomic models based on protein sequences in CASK and two Arg28 and Tyr282 residues were marked. RT‐qPCR showed lower copy numbers of CASK expression in the patients than in their parents, as well as the sex‐ and age‐ matched control groups. Patient 1 showed a skewed XCI pattern, while no related changes noted in patient 2. Conclusions Patients carrying different nonsense variants may have different degrees of different clinical phenotypes. This study expands the spectrum of genotype and phenotype correlations of CASK‐linked disorders in the Han Chinese ethnicity and provides new insights into the molecular mechanism. |
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| id | doaj.art-c7c8fa2a30fd4178bdd9f26872ba5c94 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-04-12T11:17:14Z |
| publishDate | 2022-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-c7c8fa2a30fd4178bdd9f26872ba5c942022-12-22T03:35:28ZengWileyMolecular Genetics & Genomic Medicine2324-92692022-11-011011n/an/a10.1002/mgg3.2065Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disordersKunfang Yang0Longlong Lin1Fang Yuan2Xiaoguang Li3Zhiping Liu4Xiaoping Lan5Yilin Wang6Yun Ren7Jiaoyan Li8Yucai Chen9Department of Neurology, Shanghai Children's Hospital, School of Medicine Shanghai Jiao Tong University Shanghai ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine Shanghai Jiao Tong University Shanghai ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine Shanghai Jiao Tong University Shanghai ChinaDepartment of Emergency Shanghai United Family Hospital Shanghai ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine Shanghai Jiao Tong University Shanghai ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine Shanghai Jiao Tong University Shanghai ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine Shanghai Jiao Tong University Shanghai ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine Shanghai Jiao Tong University Shanghai ChinaDepartment of Pediatrics Shanghai United Family Hospital Shanghai ChinaDepartment of Neurology, Shanghai Children's Hospital, School of Medicine Shanghai Jiao Tong University Shanghai ChinaAbstract Background The calcium/calmodulin‐dependent serine protein kinase gene (CASK) is an essential gene in mammals, critical for neurodevelopment. The purpose of this study is to expand the understanding of the diagnosis of CASK‐linked disorders. Materials/Methods From clinical and genetic mutational analyses, relevant data in 2 Han Chinese patients were collected and analyzed. Real‐time quantitative PCR (RT‐qPCR) was performed to investigate the CASK expression levels in the patients. The X‐chromosome inactivation (XCI) patterns of the patients and their nuclear families were tested by quantitation of methylation of the polymorphic human androgen receptor (HUMARA) locus. Results Two Han Chinese patients both presented with intellectual disability (ID), microcephaly with pontine and cerebellar hypoplasia (MICPCH). Two de novo mutations of c.82C>T (p.Arg28*) and c.846C>G (p.Tyr282*) in CASK have been investigated and predicted to be deleterious, which have produced truncated proteins. The functional protein association network of STRING (http://string‐db.org) generated three‐dimensional (3D) atomic models based on protein sequences in CASK and two Arg28 and Tyr282 residues were marked. RT‐qPCR showed lower copy numbers of CASK expression in the patients than in their parents, as well as the sex‐ and age‐ matched control groups. Patient 1 showed a skewed XCI pattern, while no related changes noted in patient 2. Conclusions Patients carrying different nonsense variants may have different degrees of different clinical phenotypes. This study expands the spectrum of genotype and phenotype correlations of CASK‐linked disorders in the Han Chinese ethnicity and provides new insights into the molecular mechanism.https://doi.org/10.1002/mgg3.2065CASKdevelopmental disorderHan ChinesemicrocephalyX‐chromosome inactivation |
| spellingShingle | Kunfang Yang Longlong Lin Fang Yuan Xiaoguang Li Zhiping Liu Xiaoping Lan Yilin Wang Yun Ren Jiaoyan Li Yucai Chen Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disorders Molecular Genetics & Genomic Medicine CASK developmental disorder Han Chinese microcephaly X‐chromosome inactivation |
| title | Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disorders |
| title_full | Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disorders |
| title_fullStr | Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disorders |
| title_full_unstemmed | Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disorders |
| title_short | Two heterozygous mutations in the calcium/calmodulin‐dependent serine protein kinase gene (CASK) in cases with developmental disorders |
| title_sort | two heterozygous mutations in the calcium calmodulin dependent serine protein kinase gene cask in cases with developmental disorders |
| topic | CASK developmental disorder Han Chinese microcephaly X‐chromosome inactivation |
| url | https://doi.org/10.1002/mgg3.2065 |
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