• nervous system disease
• syndromic intellectual disability

This report describes a neurodevelopmental disorder postulated to be associated with de novo variants in the CDKL1 gene. CDKL1 encodes a CDC2-related serine/threonine protein kinase. There is a single orthologous gene in Drosophila, Dmel\Cdkl; the fly gene is the single ortholog of 5 paralogous genes in human.

Loss of Drosophila Cdkl causes a semi-lethal phenotype in pupae, killing 90% of the animals just prior to eclosion. The mutant flies that survive show climbing defects, heat-induced seizures, reduced longevity, and hearing loss. Dmel\Cdkl is expressed primarily in the peripheral nervous system.

Multiple UAS constructs of the human Hsap\CDKL1 gene have been introduced into flies, including wild-type and variants implicated in this disease (see 'Disease-Implicated Variants' table below). Functional complementation (heterologous rescue) is observed: expression of wild-type Hsap\CDKL1 rescues the semi-lethality and other phenotypes of a Cdkl loss-of-function mutation.

The disease-implicated variants of Hsap\CDKL1 characterized in flies do not act like loss-of-function mutations, since they are also able to rescue semi-lethality of a Cdkl loss-of-function mutation. However, over-expression of the disease-implicated variants results in reduced longevity; over-expression of wild-type Hsap\CDKL1 does not affect longevity. These results support the hypothesis that although these variants retain some normal functionality, they act as dominant negative mutations.

[updated May 2025 by FlyBase; FBrf0222196]