Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination

Clin Genet. 2021 Aug;100(2):176-186. doi: 10.1111/cge.13973. Epub 2021 Jun 2.


We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. The lethality of the homozygote mouse prevented us from performing an assessment of locomotor behavior. The mutant heterozygote mouse; however, exhibited a significant increase in kainate-induced seizure activity over wild-type mice, supporting the hypothesis that the PKD1 variant is a candidate for the cause of the patient epilepsy. Because PKD1 was previously identified in a kinomic screen as an interacting partner of the K-Cl cotransporter 3 (KCC3), and since KCC3 is involved in peripheral nerve disease and brain hyperexcitability, one possible mechanism of action of PKD1 in disease is through KCC3. We show that catalytically inactive PKD1 stimulates KCC3 activity, consistent with tonic relief of inhibitory phosphorylation. Our findings implicate a novel role for PKD1 in the human nervous system, and uncover a mechanism that could serve as a potential target to promote nervous system myelination.

Keywords: CRISPR/Cas9; Xenopus oocytes; biotinylation; hypermyelination; kanaic acid; mouse model; myelin thickness; seizure susceptibility.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Child
  • Epilepsy / genetics*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Myelin Sheath* / metabolism
  • Myelin Sheath* / pathology
  • Oocytes / metabolism
  • Peripheral Nervous System Diseases / etiology*
  • Peripheral Nervous System Diseases / genetics
  • Potassium / metabolism
  • Protein Kinase C / genetics*
  • Protein Kinase C / metabolism
  • Rotarod Performance Test
  • Seizures / chemically induced
  • Seizures / genetics
  • Symporters / genetics
  • Symporters / metabolism
  • Xenopus laevis


  • SLC12A6 protein, human
  • Symporters
  • protein kinase D
  • Protein Kinase C
  • Potassium