Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation

Abstract

Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process.

Figure 1

CDKL5 mutation c.455G→T (p.C152F) in family 1. A, Pedigree for family 1. B, Patient II:2 at the age of 6.5 years. C, Sequence chromatograms from family members I:1, I:2, and the proband (II:2). The affected nucleotide is indicated by a blackened arrow.

Figure 2

CDKL5 mutation c.525A→T (p.R175S) in family 2. A, Pedigree for family 2. The index patient (II:2) is indicated by a blackened arrow. B, Affected twin sisters (II:2 and II:3) at the age of 41 years. Note stereotypic hand movements of the proband (II:2). C, Sequence chromatograms from the family members. From left to right: father (I:1), mother (I:2), unaffected sister (II:1), the index patient (II:2), and her MZ sister (II:3). The affected nucleotide is indicated by a blackened arrow.

Figure 3

Multiple sequence alignment of human CDKL5 with its vertebrate orthologs and with closely related human protein kinases CDKL1, CDKL2, and CDKL3 in the region of the kinase subdomains VII and VIII (see the ClustalW Web site). In the alignment, the residues that differ from the consensus sequence are shown with a gray background. The invariant DFG motif in subdomain VII and the substrate recognition sequence YVATRWYR in subdomain VIII are boxed. Affected amino acids are indicated by a blackened arrow. Amino acid substitutions are shown above the alignment.