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

ObjectiveSeveral small case series identifiedKCTD7 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.MethodsNovelKCTD7 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.ResultsPatients withKCTD7 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 publishedKCTD7 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 patientKCTD7 variants, suggesting deleterious alleles ofKCTD7 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 patho...
Source: Annals of Neurology - Category: Neurology Authors: Tags: Research Article Source Type: research