Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy
| العنوان: | Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy |
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| المؤلفون: | Yan Huang, May Christine V. Malicdan, Camilo Toro, William A. Gahl, Raman Sood, Paul G. Fisher, Gregory M. Enns, Shruti Marwaha, Edward P Frothingham, Abdel G. Elkahloun, Liliana Fernandez, Stephen B. Montgomery, Lynne A. Wolfe, Brian Harding, Elizabeth A. Burke, Thomas C. Markello, Diane B. Zastrow, Laure Fresard, Morgan L. Sturgeon, Kevin Bishop, Cameron J. Prybol, Alexander G. Bassuk, Patricia A. Ward, Christine M. Eng, Blake Carrington, Matthew T. Wheeler |
| المصدر: | Journal of Neurogenetics. 35:74-83 |
| بيانات النشر: | Informa UK Limited, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Genetics, Protein family, KCTD7, Progressive myoclonus epilepsy, Biology, medicine.disease, biology.organism_classification, Compound heterozygosity, 03 medical and health sciences, Cellular and Molecular Neuroscience, Epilepsy, 030104 developmental biology, 0302 clinical medicine, medicine, medicine.symptom, Myoclonus, Zebrafish, 030217 neurology & neurosurgery, Exome sequencing |
| الوصف: | 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. |
| تدمد: | 1563-5260 0167-7063 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::f8535b73cee19061518ba6a487c0d30a https://doi.org/10.1080/01677063.2021.1892095 |
| رقم الأكسشن: | edsair.doi...........f8535b73cee19061518ba6a487c0d30a |
| قاعدة البيانات: | OpenAIRE |
PDF full text from Publisher | تدمد: | 15635260 01677063 |
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