Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder

CDKL5 is a kinase with relevant functions in correct neuronal development and in the shaping of synapses. A decrease in its expression or activity leads to a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD). CDD arises from CDKL5 mutations that lie in the coding region of the gene. However, the identification of a SNP in the CDKL5 5 ' UTR in a patient with symptoms consistent with CDD, together with the complexity of the CDKL5 transcript leader, points toward a relevant translational regulation of CDKL5 expression with important consequences in physiological processes as well as in the pathogenesis of CDD. We performed a bioinformatics and molecular analysis of the 5'UTR of CDKL5 to identify translational regulatory features. We propose an important role for structural cis-acting elements, with the involvement of the eukaryotic translational initiation factor eIF4B. By evaluating both cap-dependent and cap-independent translation initiation, we suggest the presence of an IRES supporting the translation of CDKL5 mRNA and propose a pathogenic effect of the C>T -189 SNP in decreasing the translation of the downstream protein.

Automated summary

CDKL5 is an important kinase involved in neuronal development and synapse formation. Decreased expression or activity of CDKL5 leads to severe neurodevelopmental disorders. This study investigates the translational regulation of CDKL5 and identifies important elements and factors involved. The findings provide insights into the physiological processes and pathogenesis related to CDKL5 deficiency disorder.