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The clinical spectrum and neurodevelopmental pathogenesis of KPTN-related disorder in a mouse model

Objective Pathogenic variants in Kaptin (KPTN) cause KPTN-related disorder (KRD). KPTN modulates mTOR signaling activation within the KICSTOR complex in response to cellular amino acid levels. We define the clinical spectrum and investigate the developmental pathogenesis of KRD. Methods We report th...

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Main Authors: Rawlins, Lettie (Author) , Iffland II, Philip H. (Author) , Page, John (Author) , Flessner, Rebecca Z. (Author) , Elziny, Soad M. (Author) , Sbornova, Irina (Author) , Babus, Janice K. (Author) , Bruckmeier, Sophie R. (Author) , Parikh, Ria (Author) , Verhoeven, Merel (Author) , Fasham, James (Author) , Leslie, Joseph S. (Author) , Caswell, Richard (Author) , Ubeyratna, Nishanka (Author) , Wenger, Olivia (Author) , Scott, Ethan M. (Author) , Schreiber, John (Author) , Syrbe, Steffen (Author) , Klabunde-Cherwon, Annick (Author) , Owens, Martina (Author) , Crosby, Andrew H. (Author) , Baple, Emma L. (Author) , Crino, Peter B. (Author)
Format: Article (Journal)
Language:English
Published: 16 February 2026
In: Annals of neurology
Year: 2026, Pages: 1-16
ISSN:1531-8249
DOI:10.1002/ana.78159
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/ana.78159
Verlag, Lf, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.78159
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Author Notes:Lettie E. Rawlins, MBChB, PhD, Philip H. Iffland II, John Page, MS, Rebecca Z. Flessner, MD, Soad M. Elziny, PhD, Irina Sbornova, BS, Janice K. Babus, BA, Sophie R. Bruckmeier, PhD, Ria Parikh, BS, Merel Verhoeven, BS, James Fasham, MBChB, PhD, Joseph S. Leslie, PhD, Richard Caswell, PhD, Nishanka Ubeyratna, MSc, Olivia Wenger, MD, Ethan M. Scott, MD, John Schreiber, MD, Steffen Syrbe, MD, PhD, Annick Klabunde-Cherwon, MD, Martina Owens, BSc Hons, MSc, Andrew H. Crosby, PhD, Emma L. Baple, BBS, PhD, Peter B. Crino, MD, PhD, and the KPTN Consortium
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Summary:Objective Pathogenic variants in Kaptin (KPTN) cause KPTN-related disorder (KRD). KPTN modulates mTOR signaling activation within the KICSTOR complex in response to cellular amino acid levels. We define the clinical spectrum and investigate the developmental pathogenesis of KRD. Methods We report the genotype and clinical phenotype of 71 KRD individuals (28 female subjects, ages 1 to 55 years) including 48 newly identified KRD individuals. The effects of Kptn knockout on brain development were assayed in vitro and in vivo. Results We defined 15 novel KPTN variants. Intellectual disability (ID) was identified in all KRD individuals. Macrocephaly and epilepsy were observed in 46% and 47%, respectively. Neuroimaging revealed megalencephaly but no overt structural abnormalities. Ketotic hypoglycemia and endocrinopathies were identified in KRD. Increased head size was detected in unaffected parents heterozygous for KPTN variants. Two KRD individuals with drug-resistant epilepsy were treated with the mTOR inhibitor sirolimus but did not exhibit improved seizure control. CRISPR/Cas9 Kptn knockout in vitro induced mTOR activation and an mTOR-dependent increase in cell size. Kptn−/− mice exhibited increased cortical mTOR signaling that was reduced by rapamycin. Heterotopic neurons were identified in the subcortical white matter in the Kptn −/− mouse. Focal CRISPR/Cas9 Kptn knockout in cortex via in utero electroporation resulted in white matter heterotopic neurons. Electroencephalogram (EEG) did not detect ictal or inter-ictal abnormalities. Interpretation KRD is a multisystem neurodevelopmental disorder associated with ID, macrocephaly, epilepsy, mTOR signaling hyperactivation, and in a mouse model, subtle structural alterations in cerebral cortical cytoarchitecture.
Item Description:Gesehen am 08.04.2026
Physical Description:Online Resource
ISSN:1531-8249
DOI:10.1002/ana.78159

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