Elizabeth A Burke, Morgan Sturgeon, Diane B Zastrow, Liliana Fernandez, Cameron Prybol, Shruti Marwaha, Edward P Frothingham, Patricia A Ward, Christine M Eng, Laure Fresard, Stephen B Montgomery, Gregory M Enns, Paul G Fisher, Lynne A Wolfe, Brian Harding, Blake Carrington, Kevin Bishop, Raman Sood, Yan Huang, Abdel Elkahloun, Camilo Toro, Alexander G Bassuk, Matthew T Wheeler, Thomas C Markello, William A Gahl, May Christine V Malicdan
{"title":"进行性肌阵挛性癫痫的复合杂合KCTD7变异。","authors":"Elizabeth A Burke, Morgan Sturgeon, Diane B Zastrow, Liliana Fernandez, Cameron Prybol, Shruti Marwaha, Edward P Frothingham, Patricia A Ward, Christine M Eng, Laure Fresard, Stephen B Montgomery, Gregory M Enns, Paul G Fisher, Lynne A Wolfe, Brian Harding, Blake Carrington, Kevin Bishop, Raman Sood, Yan Huang, Abdel Elkahloun, Camilo Toro, Alexander G Bassuk, Matthew T Wheeler, Thomas C Markello, William A Gahl, May Christine V Malicdan","doi":"10.1080/01677063.2021.1892095","DOIUrl":null,"url":null,"abstract":"<p><p>KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified <i>KCTD7</i> compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate <i>kctd7</i> knockout zebrafish. <i>Kctd7</i> homozygous mutants showed global dysregulation of gene expression and increased transcription of <i>c-fos</i>, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of <i>KCTD7</i>-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":"35 2","pages":"74-83"},"PeriodicalIF":1.8000,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1892095","citationCount":"1","resultStr":"{\"title\":\"Compound heterozygous <i>KCTD7</i> variants in progressive myoclonus epilepsy.\",\"authors\":\"Elizabeth A Burke, Morgan Sturgeon, Diane B Zastrow, Liliana Fernandez, Cameron Prybol, Shruti Marwaha, Edward P Frothingham, Patricia A Ward, Christine M Eng, Laure Fresard, Stephen B Montgomery, Gregory M Enns, Paul G Fisher, Lynne A Wolfe, Brian Harding, Blake Carrington, Kevin Bishop, Raman Sood, Yan Huang, Abdel Elkahloun, Camilo Toro, Alexander G Bassuk, Matthew T Wheeler, Thomas C Markello, William A Gahl, May Christine V Malicdan\",\"doi\":\"10.1080/01677063.2021.1892095\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified <i>KCTD7</i> compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate <i>kctd7</i> knockout zebrafish. <i>Kctd7</i> homozygous mutants showed global dysregulation of gene expression and increased transcription of <i>c-fos</i>, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of <i>KCTD7</i>-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.</p>\",\"PeriodicalId\":16491,\"journal\":{\"name\":\"Journal of neurogenetics\",\"volume\":\"35 2\",\"pages\":\"74-83\"},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2021-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1080/01677063.2021.1892095\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of neurogenetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/01677063.2021.1892095\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2021/5/10 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of neurogenetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/01677063.2021.1892095","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2021/5/10 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy.
KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.
期刊介绍:
The Journal is appropriate for papers on behavioral, biochemical, or cellular aspects of neural function, plasticity, aging or disease. In addition to analyses in the traditional genetic-model organisms, C. elegans, Drosophila, mouse and the zebrafish, the Journal encourages submission of neurogenetic investigations performed in organisms not easily amenable to experimental genetics. Such investigations might, for instance, describe behavioral differences deriving from genetic variation within a species, or report human disease studies that provide exceptional insights into biological mechanisms