Journal article
Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy
Journal of neurogenetics, Vol.35(2), pp.74-83
05/10/2021
DOI: 10.1080/01677063.2021.1892095
PMID: 33970744
Abstract
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.
Keywords: KCTD7; progressive myoclonic epilepsy; seizure; thalamus; zebrafish.
Details
- Title: Subtitle
- Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy
- Creators
- Elizabeth A Burke - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USAMorgan Sturgeon - Department of Pediatrics, University of Iowa, Iowa City, IA, USADiane B Zastrow - Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USALiliana Fernandez - Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USACameron Prybol - Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USAShruti Marwaha - Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USAEdward P Frothingham - Mid-Valley Children’s Clinic, Albany, OR, USAPatricia A Ward - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USAChristine M Eng - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USALaure Fresard - Department of Pathology, Stanford University School of Medicine, Stanford, CA, USAStephen B Montgomery - Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA, Department of Genetics, Stanford University School of Medicine, Stanford, CA, USAGregory M Enns - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USAPaul G Fisher - Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA, Department of Neurology, Stanford University School of Medicine, Stanford, CA, USALynne A Wolfe - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USABrian Harding - Departments of Pathology and Lab Medicine (Neuropathology), Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USABlake Carrington - Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USAKevin Bishop - Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USARaman Sood - Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USAYan Huang - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USAAbdel Elkahloun - Microarray Core, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USACamilo Toro - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USAAlexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, IA, USAMatthew T Wheeler - Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USAThomas C Markello - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USAWilliam A Gahl - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USAMay Christine V Malicdan - NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA
- Resource Type
- Journal article
- Publication Details
- Journal of neurogenetics, Vol.35(2), pp.74-83
- DOI
- 10.1080/01677063.2021.1892095
- PMID
- 33970744
- ISSN
- 0167-7063
- eISSN
- 1563-5260
- Grant note
- DOI: 10.13039/100000051, name: National Human Genome Research Institute; name: Common Fund of the Office of the Director of the National Institutes of Health, award: U01HG007708, U01HG010218, U01HG007709, U01HG007530, U01HG007942, U01HG007690, U01HG007672; name: Stanford Clinical and Translational Science Award, award: UL1TR001085, R01NS098590
- Language
- English
- Date published
- 05/10/2021
- Academic Unit
- Neurology; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984077377202771
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