The Clinical Spectrum and Neurodevelopmental Pathogenesis of KPTN-Related Disorder in a Mouse Model - PubMed
5 days ago
- #KPTN gene
- #mTOR signaling
- #neurodevelopmental disorder
- KPTN-related disorder (KRD) is caused by pathogenic variants in Kaptin (KPTN), affecting mTOR signaling.
- Clinical features of KRD include intellectual disability (100%), macrocephaly (46%), and epilepsy (47%).
- Neuroimaging in KRD shows megalencephaly without overt structural abnormalities.
- Ketotic hypoglycemia and endocrinopathies are also observed in KRD patients.
- Unaffected parents with KPTN variants show increased head size.
- Two KRD patients with drug-resistant epilepsy did not respond to mTOR inhibitor sirolimus.
- CRISPR/Cas9 Kptn knockout in vitro leads to mTOR activation and increased cell size.
- Kptn-/- mice exhibit increased cortical mTOR signaling, reduced by rapamycin, and show heterotopic neurons.
- Focal CRISPR/Cas9 Kptn knockout in mouse cortex results in white matter heterotopic neurons.
- EEG in Kptn-/- mice shows no ictal or inter-ictal abnormalities.
- KRD is a multisystem neurodevelopmental disorder with ID, macrocephaly, epilepsy, and mTOR hyperactivation.