The Clinical Spectrum and Neurodevelopmental Pathogenesis of KPTN-Related Disorder in a Mouse Model

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Developmental Biology

Background:

• Pathogenic variants in the KPTN gene cause KPTN-related disorder (KRD).
• KPTN plays a role in regulating mTOR signaling in response to amino acid levels.
• Understanding the clinical spectrum and pathogenesis of KRD is crucial.

Purpose of the Study:

• To define the clinical spectrum of KPTN-related disorder (KRD).
• To investigate the developmental pathogenesis of KRD.
• To explore the role of KPTN in mTOR signaling and brain development.

Main Methods:

• Genotype and phenotype data were collected from 71 KRD individuals.
• Kptn knockout models (in vitro and in vivo) were used to study brain development.
• Clinical data, neuroimaging, and molecular assays were employed.

Main Results:

• Fifteen novel KPTN variants were identified, all associated with intellectual disability.
• Macrocephaly (46%) and epilepsy (47%) were common; neuroimaging showed megalencephaly.
• Kptn knockout led to mTOR activation, increased cell size, and heterotopic neurons in mice.

Conclusions:

• KRD is a multisystem neurodevelopmental disorder characterized by ID, macrocephaly, and epilepsy.
• The disorder is linked to mTOR signaling hyperactivation.
• Mouse models reveal subtle cerebral cortical cytoarchitectural alterations in KRD.