Mutations in the C-terminus of CDKL5: proceed with caution

Abstract

Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. Milder phenotypes have been associated with sequence variations in the 3'-end of the CDKL5 gene. Identification of novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region strongly questions the eventual pathogenicity of sequence variations located in the 3'-end of the gene. We investigated a group of 30 female patients with a clinically heterogeneous phenotype ranging from nonspecific intellectual disability to a severe neonatal encephalopathy and identified two heterozygous CDKL5 missense mutations, the previously reported p.Val999Met and the novel mutation p.Pro944Thr. However, these mutations have also been detected in their healthy father. Considering our results and all data from the literature, we suggest that genetic variations beyond the codon 938 in human CDKL5115 protein may have minor or no significance. It is probable that screening of exons 19-21 of the CDKL5 gene is not useful in practical molecular diagnosis of atypical Rett syndrome.

Figure 1

Fluorescence sequence analysis of exon 20 of the CDKL5 gene using the forward primers. The arrow indicates the position of the p.Pro944Thr variant in exon 20.

Figure 2

Schematic representation of CDKL5. (a) Schematic representation of the human CDKL5 gene. CDKL5 exons are indicated by boxes. The three non-coding exons are shown hatched, and the new exon 16b is shown in dark grey. Mutations/variants in the 3′-end of CDKL5 reported to date are indicated corresponding to their location within the gene. (b) Human CDKL5 protein isoforms differing in the C-terminal region. Functional domains and signatures are indicated: ATP-binding domain (aa 19–43); serine threonine kinase active site (aa 131–143); TEY motif (aa 169–171), putative signal peptidase I serine active site (aa 971–978). CDKL5₁₁₅ contains the primate-specific exons 19–21. In CDKL5₁₀₇, 170 nucleotides of intron 18 are retained.