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

Metz KA¹, Teng X^1,2, Coppens I¹, Lamb HM¹, Wagner BE³, Rosenfeld JA⁴, Chen X², Zhang Y², Kim HJ⁵, Meadow ME⁵, Wang TS^1,6, 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 JM^1,6,29.

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:

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.