ClinVar

In 2 Mexican sibs with infantile onset of progressive myoclonic epilepsy (EPM3; 611726) and intracellular inclusions, consistent with a diagnosis of neuronal ceroid lipofuscinosis (designated CLN14), Staropoli et al. (2012) identified a homozygous 550C-T transition in exon 4 of the KCTD7 gene, resulting in an arg184-to-cys (R184C) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for the mutation, which was not found in over 6,000 controls. In cerebellar cells, wildtype KCTD7 showed broad, punctate cytoplasmic localization and distinct signal at the plasma membrane, whereas mutant A184C showed more diffuse cytoplasmic localization, markedly diminished signaling at the plasma membrane, and prominent cytoplasmic aggregates. These results suggested that the mutation affects the trafficking and/or solubility of KCTD7. Studies in HEK293T cells showed that the R184C mutation abrogated the interaction with cullin-3 (CUL3; 603136), which Staropoli et al. (2012) suggested may lead to an accumulation of toxic intracellular proteins.