Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination.
Salma OmerSheng Chih JinRainelli KoumangoyeStephanie M RobertDaniel DuranCarol Nelson-WilliamsAnita HuttnerMichael DiLunaKristopher T KahleEric DelpirePublished in: Clinical genetics (2021)
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.
Keyphrases
- peripheral nerve
- polycystic kidney disease
- protein kinase
- wild type
- endothelial cells
- crispr cas
- case report
- multiple sclerosis
- high glucose
- spinal cord injury
- pluripotent stem cells
- genome editing
- high throughput
- dna damage
- hiv infected
- temporal lobe epilepsy
- insulin resistance
- antiretroviral therapy
- brain injury
- blood brain barrier
- cerebral ischemia