Metz KA1, Teng X1,2, Coppens I1, Lamb HM1, Wagner BE3, Rosenfeld JA4, Chen X2, Zhang Y2, Kim HJ5, Meadow ME5, Wang TS1,6, Haberlandt ED7, Anderson GW8, Leshinsky-Silver E9, Bi W4, Markello TC10, Pratt M11, Makhseed N12, Garnica A13, Danylchuk NR13, Burrow TA13, Jayakar P14, McKnight D15, Agadi S16, Gbedawo H17, Stanley C18, Alber M19, Prehl I20, Peariso K21, Ong MT22, Mordekar SR22, Parker MJ23, Crooks D24, Agrawal PB25, Berry GT25, Loddenkemper T26, Yang Y4, Maegawa GHB27, Aouacheria A28, Markle JG1, Wohlschlegel JA5, Hartman AL29, Hardwick JM1,6,29.
Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function.
Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples.
Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology.
Bi-allelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7. This article is protected by copyright. All rights reserved.
- Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Balimore, Maryland, united States of America.
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Collge of Pharmaceutical Sciences, Soochow university, Suzhou, Jiangsu Province, People’s Republic of China.
- Histopathology Department, Royal Hallamshire Hospital, Sheffield, United Kingdom.
- Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
- Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
- Clinical Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria, Department of Child and Youth Health, Hospital of Dornbirn, Dornbirn, Austria.
- Histopathology Department, Great Ormond Street Hospital for Children, London, United Kingdom.
- Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel.
- NIH Undiagnosed Dieases Program, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
- Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, United States of America.
- Department of Pediatrics, Jahra Hospital, Ministry of Health, Kuwait.
- Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Arkansas, United States of America.
- Division of Genetics and Metabolism, Nicklaus Children’s Hospital, Miami, Florida, United States of America.
- GeneDx Gaithersburg, Maryland, United States of America.
- Department of Neurology, Texas Children’s Hospital, Houston, Texas, United States of America.
- Vital Kids Medicine PLLC, Seattle, Washington, United States of America.
- Courtagen Life Sciences, Woburn, Massachusetts, United States of America.
- Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany.
- Practice for Human Genetics, CeGaT GmbH, Tübingen, Germany.
- Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America.
- Department of Paediatric Neurology, Sheffield Children’s Hospital National Health Service Foundation Trust, Sheffield, United Kingdom.
- Sheffield Clinical Genetics Service, Sheffield Children’s Hospital National Health Service Foundation Trust, Western Bank, Sheffield, United Kingdom.
- Department of Neuropathology, the Walton Centre National Health Service Foundation Trust, Liverpool, United Kingdom.
- Division of Genetics and Genomics, te Manton Center for Orphan Disease Research, Boston Children’s Hsopital, Harvard Medical School, Boston, Massachusetts, United States of America.
- Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts, United States of America.
- Department of Pediatrics/Genetics & Metabolism, University of Florida, Gainesville, Florida, United States of America.
- ISEM, Institut des Sciences de l’Evolution de Montpellier, Université de Montpellier, CNRS, EPHE, IRD, Montpellier, 34095, France.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.