Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy.

Autor: Burke EA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA., Sturgeon M; Department of Pediatrics, University of Iowa, Iowa City, IA, USA., Zastrow DB; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA., Fernandez L; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA., Prybol C; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA., Marwaha S; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA., Frothingham EP; Mid-Valley Children's Clinic, Albany, OR, USA., Ward PA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Eng CM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Fresard L; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Montgomery SB; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Enns GM; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Fisher PG; 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, USA., Wolfe LA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA., Harding B; Departments of Pathology and Lab Medicine (Neuropathology), Children's Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Carrington B; Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA., Bishop K; Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA., Sood R; Zebrafish Core, Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA., Huang Y; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA., Elkahloun A; Microarray Core, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA., Toro C; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA., Bassuk AG; Department of Pediatrics, University of Iowa, Iowa City, IA, USA., Wheeler MT; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA., Markello TC; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA., Gahl WA; 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, USA., Malicdan MCV; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Jazyk: angličtina
Zdroj: Journal of neurogenetics [J Neurogenet] 2021 Mar-Jun; Vol. 35 (2), pp. 74-83. Date of Electronic Publication: 2021 May 10.
DOI: 10.1080/01677063.2021.1892095
Abstrakt: 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.
Databáze: MEDLINE
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