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KCTD7 encodes a BTB/POZ and poxvirus + zinc finger domain-containing protein highly expressed in neuronal tissues. Biallelic pathogenic variants in KCTD7 cause autosomal recessive progressive myoclonic epilepsy type 3 (PME3), characterized by seizure onset in infancy, myoclonus, neuroregression and abnormal EEG activity. Onset typically occurs after a period of normal development with subsequent treatment-resistant myoclonic and tonic-clonic seizures. This genotype–phenotype correlation is supported by consistent findings across multiple independent cohorts and functional studies in cellular and animal models.
The initial multi-patient series described four affected individuals from three consanguineous families with homozygous missense variants such as c.280C>T (p.Arg94Trp) (PMID:34866617). All variants segregated with disease under an autosomal recessive mode and were absent or extremely rare in population databases. Clinical hallmarks included early-onset myoclonus, generalized hypotonia, brisk reflexes, and characteristic EEG abnormalities (PMID:34866617).
Beyond these key missense alleles, PME3 is associated with a spectrum of variant classes including canonical splice-site changes, frameshift deletions (e.g., c.696del (p.Phe232LeufsTer?)), and large genomic rearrangements. The p.Arg94Trp and nearby p.Arg94Gln alleles recur in multiple consanguineous pedigrees, suggesting potential founder events in specific populations.
Mechanistic studies demonstrate that wild-type KCTD7 interacts with Cullin-3 to regulate neuronal resting membrane potential: heterologous expression of KCTD7 hyperpolarizes neurons, whereas the p.Arg84Trp variant diminishes this effect and increases excitability (PMID:21710140). Xenopus laevis oocyte assays revealed that the p.Phe232LeufsTer? frameshift variant abolishes K+ fluxes and disrupts SAT2-dependent glutamine transport, mirroring altered neurotransmitter homeostasis (PMID:27742667).
An in vivo knockout zebrafish model produced by zinc finger nucleases recapitulates key features of human PME3, including c-fos upregulation and seizure-like behavior, establishing an organismal system for therapeutic screening (PMID:33970744).
Although mutations in KCTD7 also underlie CLN14 neuronal ceroid lipofuscinosis and Unverricht-Lundborg syndrome, distinct clinical and pathological features such as lysosomal inclusions or ataxia differentiate these conditions from PME3. No refuting evidence has been reported for the specific association with PME3 under biallelic inheritance.
Collectively, the genetic and experimental concordance across families, models, and mechanistic assays supports a strong clinical validity for KCTD7–PME3. Early genetic diagnosis facilitates targeted management and inclusion in therapeutic trials.
Gene–Disease AssociationStrong4 unrelated probands from 3 families, autosomal recessive segregation and concordant functional data Genetic EvidenceModerateFour probands with biallelic missense variants in 3 families; segregation under autosomal recessive inheritance; absent in controls ([PMID:34866617]) Functional EvidenceStrongMultiple functional assays (patch clamp, oocyte K+ flux, zebrafish knockout) demonstrate loss-of-function concordant with human phenotype |