CDKL5 Deficiency Disorder: Revealing the Molecular Mechanism of Pathogenic Variants

• Published in: International journal of molecular sciences Vol. 26; no. 17; p. 8399
• Main Authors: Paul, Shamrat Kumar, Panday, Shailesh Kumar, Boccuto, Luigi, Alexov, Emil
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.09.2025
• Subjects: Convulsions & seizures; Cyclin-dependent kinases; Datasets; Epilepsy; Epileptic Syndromes - genetics; Epileptic Syndromes - metabolism; Genomes; Humans; Kinases; Localization; Males; Models, Molecular; Muscle Hypotonia - genetics; Mutation, Missense; Neurodevelopmental disorders; Ostomy; Phosphorylation; Protein Binding; Protein Conformation; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - deficiency; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Spasms, Infantile - genetics; Spasms, Infantile - metabolism; Thermodynamics; X chromosomes; 3D structure model; CDKL5; in silico modeling; pathogenic variant; folding free energy; binding free energy; CDKL5 deficiency syndrome; missense mutation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms26178399

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, which is a developmental and epileptic encephalopathy occurring in 1 in every 40,000 to 60,000 live births, was the subject of this computational investigation. This study provided a comprehensive list of missense variants (156) seen in the human population within the CDKL5 protein. Furthermore, the list of CDKL5 binding partners was updated to include four new entries. Computational modeling resulted in 3D structure models of twenty-four CDKL5-target protein complexes. The CDKL5 stability changes upon the above-mentioned missense mutations that were modeled, and it was shown that the corresponding folding free energy changes (ΔΔGfolding) caused by pathogenic variants are much larger than the ΔΔGfolding caused by benign variants. The same observation was made for the binding free energy change (ΔΔGbinding). This resulted in a protocol that allowed for the reclassification of missense variants with unknown or conflicting significance into pathogenic or benign. It was demonstrated that such reclassification is more reliable than using leading tools for pathogenicity predictions, since the latter failed to correctly predict known pathogenic/benign variants. Furthermore, the study demonstrated that pathogenicity is linked with the disturbance of thermodynamics quantities such as ΔΔGfolding and ΔΔGbinding, paving the way for development of therapeutic solutions.