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

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.

SUBMITTER: Metz KA

PROVIDER: S-EPMC6295419 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Metz Kyle A KA Teng Xinchen X Coppens Isabelle I Lamb Heather M HM Wagner Bart E BE Rosenfeld Jill A JA Chen Xianghui X Zhang Yu Y Kim Hee Jong HJ Meadow Michael E ME Wang Tim Sen TS Haberlandt Edda D ED Anderson Glenn W GW Leshinsky-Silver Esther E Bi Weimin W Markello Thomas C TC Pratt Marsha M Makhseed Nawal N Garnica Adolfo A Danylchuk Noelle R NR Burrow Thomas A TA Jayakar Parul P McKnight Dianalee D Agadi Satish S Gbedawo Hatha H Stanley Christine C Alber Michael M Prehl Isabelle I Peariso Katrina K Ong Min Tsui MT Mordekar Santosh R SR Parker Michael J MJ Crooks Daniel D Agrawal Pankaj B PB Berry Gerard T GT Loddenkemper Tobias T Yang Yaping Y Maegawa Gustavo H B GHB Aouacheria Abdel A Markle Janet G JG Wohlschlegel James A JA Hartman Adam L AL Hardwick J Marie JM

Annals of neurology 20181108 5

<h4>Objective</h4>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.<h4>Methods< ...[more]

PMID: 30295347

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Project description:Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.

Dataset Information

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

Publications

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

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