CDKL5 – Atypical Rett Syndrome

CDKL5 is an X-linked serine/threonine kinase essential for neuronal development and morphogenesis. Heterozygous loss-of-function variants in CDKL5 cause early-onset epileptic encephalopathy and an atypical Rett syndrome variant characterized by infantile seizures, severe developmental delay, and Rett-like features. The mode of inheritance is X-linked dominant, with most pathogenic alleles arising de novo in females.

Genetic screening revealed de novo CDKL5 mutations in 3 of 83 Czech patients with early-onset seizures and severe intellectual disability [(PMID:27187038)] and in 11 of 177 French women with infantile spasms and atypical Rett features [(PMID:19793311)], totaling 14 unrelated probands. These studies expand the genetic evidence for CDKL5 in atypical Rett syndrome from limited case reports to sizeable cohorts.

The variant spectrum includes frameshift and splice-site alterations (e.g., c.1757_1758del (p.Ser586CysfsTer24)) and missense substitutions clustered in the kinase domain. No clear genotype–phenotype correlations have emerged beyond recurrent hotspots at p.Ala40 and p.Arg178, and no population-specific founder alleles have been identified.

In vitro kinase assays demonstrate that Rett-associated CDKL5 variants abolish autophosphorylation and phosphorylation of MeCP2, confirming loss of catalytic activity [(PMID:16935860)]. Cellular localization experiments show that de novo missense mutations mislocalize CDKL5 to the cytoplasm, correlating with severe neurodevelopmental impairment [(PMID:17993579)].

Neuronal models reveal that CDKL5 regulates dendritic arborization via Rac1 signaling, with RNAi knockdown impairing neurite outgrowth and overexpression enhancing dendritic complexity in rodent neurons [(PMID:20861382)]. Quantitative phosphoproteomics identified MAP1S (Ser900) and CEP131 (Ser35) as physiological substrates, illuminating CDKL5’s role in microtubule and centrosome function [(PMID:30266825)].

Integration of genetic and functional data supports a Definitive ClinGen classification for CDKL5 in atypical Rett syndrome. Clinical testing of CDKL5 is recommended for females presenting with early-onset seizures and Rett-like features to guide diagnosis and management. Key Take-home: CDKL5 mutational analysis is of high clinical utility in atypical Rett syndrome.

References

• Folia biologica • 2016 • Novel CDKL5 Mutations in Czech Patients with Phenotypes of Atypical Rett Syndrome and Early-Onset Epileptic Encephalopathy. PMID:27187038
• Clinical genetics • 2009 • Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature. PMID:19793311
• The Journal of biological chemistry • 2006 • Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation. PMID:16935860
• Journal of medical genetics • 2008 • Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. PMID:17993579
• The Journal of neuroscience • 2010 • CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling. PMID:20861382
• The EMBO journal • 2018 • Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase. PMID:30266825

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