CDKL5 – West Syndrome

Cyclin-dependent kinase-like 5 (CDKL5) is an X-linked serine/threonine kinase highly expressed in neurons, with de novo truncating and missense mutations causing early-onset epileptic encephalopathy overlapping with West Syndrome features such as infantile spasms and hypsarrhythmia (PMID:16813600).

Inheritance is X-linked with predominantly de novo variants in females and rare somatic mosaicism in males. To date, over 100 unrelated probands across more than ten independent cohorts have been reported with CDKL5 variants presenting West Syndrome (PMID:18790821, PMID:31122804). Familial segregation beyond de novo occurrence is limited, supporting a dominant loss-of-function mechanism.

The variant spectrum includes truncating frameshift and nonsense mutations in both the catalytic domain and C-terminal region (e.g., c.2788insG (p.Glu930GlyfsTer9)) (PMID:30236769), recurrent missense changes in the kinase domain (c.119C>T (p.Ala40Val)) (PMID:17993579), and Alu-mediated microdeletions affecting exons 1–4 (PMID:19471977).

Functional studies reveal that Rett-associated and West Syndrome-associated CDKL5 mutations impair kinase activity and alter subcellular localization: mutant proteins show both reduced and aberrant autophosphorylation of the TEY activation motif, disrupted MeCP2 phosphorylation, and cytoplasmic mislocalization (PMID:16935860, PMID:17993579). In neuronal models, CDKL5 deficiency compromises Rac1-dependent dendritic arborization and neurite outgrowth, mirroring patient phenotypes (PMID:20861382).

Therapeutic splice modulation using engineered U1snRNAs restores correct CDKL5 splicing, protein expression, and kinase activity in vitro (PMID:31450582). Aminoglycoside-mediated read-through of premature termination codons partially rescues subcellular localization but yields variable restoration of catalytic function (PMID:31232219).

Although consanguineous siblings with idiopathic West Syndrome lacked CDKL5 mutations, highlighting genetic heterogeneity (PMID:21559165), the repeated identification of de novo CDKL5 variants in infantile spasms cohorts substantiates its primary role in X-linked West Syndrome.

Integration of genetic and functional data supports haploinsufficiency as the predominant mechanism. CDKL5 testing is indicated in infants with West Syndrome for diagnostic confirmation and to inform emerging genotype-directed therapies.

Key Take-home: CDKL5 loss-of-function variants are a significant cause of X-linked West Syndrome, and mechanistic insights have catalyzed development of targeted RNA-based and read-through therapeutic strategies.

References

• Clinical genetics • 2006 • Maternal origin of a novel C-terminal truncation mutation in CDKL5 causing a severe atypical form of Rett syndrome PMID:16813600
• Brain • 2008 • Key clinical features to identify girls with CDKL5 mutations. PMID:18790821
• Brain & development • 2019 • Phenotypic manifestations between male and female children with CDKL5 mutations. PMID:31122804
• International journal of developmental neuroscience • 2019 • A novel C-terminal truncated mutation in hCDKL5 protein causing a severe West syndrome: Comparison with previous truncated mutations and genotype/phenotype correlation. PMID:30236769
• Journal of medical genetics • 2008 • Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. PMID:17993579
• 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
• The Journal of neuroscience • 2010 • CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling. PMID:20861382
• Neurogenetics • 2009 • Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder. PMID:19471977
• RNA biology • 2019 • Aminoglycoside drugs induce efficient read-through of CDKL5 nonsense mutations, slightly restoring its kinase activity. PMID:31232219
• International journal of molecular sciences • 2019 • Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy. PMID:31450582
• Journal of pediatric neurosciences • 2010 • Two female siblings with West syndrome: Familial idiopathic West syndrome with genetic susceptibility and variable phenotypic expression. PMID:21559165

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