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Ann Neurol. 2018 Nov;84(5):766-780. doi: 10.1002/ana.25351. Epub 2018 Nov 8.

KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect.

Author information

1
Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
2
Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
3
Histopathology Department, Royal Hallamshire Hospital, Sheffield, United Kingdom.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
5
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA.
6
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
7
Clinical Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.
8
Department of Child and Youth Health, Hospital of Dornbirn, Dornbirn, Austria.
9
Histopathology Department, Great Ormond Street Hospital for Children, London, United Kingdom.
10
Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel.
11
NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
12
Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK.
13
Department of Pediatrics, Jahra Hospital, Ministry of Health, Al Jahra, Kuwait.
14
Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR.
15
Division of Genetics and Metabolism, Nicklaus Children's Hospital, Miami, FL.
16
GeneDx, Gaithersburg, MD.
17
Department of Neurology, Texas Children's Hospital, Houston, TX.
18
Vital Kids Medicine, Seattle, WA.
19
Courtagen Life Sciences, Woburn, MA.
20
Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany.
21
Practice for Human Genetics, CeGaT, Tübingen, Germany.
22
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
23
Department of Paediatric Neurology, Sheffield Children's National Health Service Foundation Trust, Sheffield, United Kingdom.
24
Sheffield Clinical Genetics Service, Sheffield Children's National Health Service Foundation Trust, Sheffield, United Kingdom.
25
Department of Neuropathology, Walton Centre National Health Service Foundation Trust, Liverpool, United Kingdom.
26
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA.
27
Department of Neurology, Boston Children's Hospital, Boston, MA.
28
Department of Pediatrics/Genetics and Metabolism, University of Florida, Gainesville, FL.
29
Montpellier Institute of Evolution Sciences, University of Montpellier, CNRS, EPHE, IRD, Montpellier, France.
30
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

INTERPRETATION:

Biallelic 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. Ann Neurol 2018;84:774-788.

PMID:
30295347
DOI:
10.1002/ana.25351

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