Rett syndrome is a severe
neurodevelopmental disorder, almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Both the classic and atypical forms of
Rett syndrome are primarily due to mutations in the
methyl-CpG-binding protein 2 (MECP2) gene. Mutations in the X-linked
cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with
atypical Rett syndrome,
X-linked infantile spasms sharing common features of generally early-onset
seizures and
mental retardation. CDKL5 is known as
serine/threonine protein kinase 9 (STK9) and is mapped to the Xp22 region. It has a conserved
serine/threonine kinase domain within its amino terminus and a large C-terminal region. Disease-causing mutations are distributed in both the amino terminal domain and in the large C-terminal domain. We have screened the CDKL5 gene in 44 patients with
atypical Rett syndrome who had tested negative for MECP2 gene mutations and have identified 6 sequence variants, out of which three were novel and three known mutations. Two of these novel mutations p.V966I and p.A1011V were missense and p.H589H a silent mutation. Other known mutations identified were p.V999M, p.Q791P and p.T734A. Sequence homology for all the mutations revealed that the two mutations (p.Q791P and p.T734A) were conserved across species. This indicated the importance of these residues in structure and function of the
protein. The damaging effects of these mutations were analysed in silico using PolyPhen-2 online software. The PolyPhen-2 scores of p.Q791P and p.T734A were 0.998 and 0.48, revealing that these mutations could be deleterious and might have potential functional effect. All other mutations had a low score suggesting that they might not alter the activity of CDKL5. We have also analysed the position of the mutations in the CDKL5
protein and found that all the mutations were present in the C-terminal domain of the
protein. The C-terminal domain is required for cellular localization through
protein-
protein interaction; any mutations in this domain might alter this function of the
protein. This is the first report from India showing the mutation in CDKL5 gene in Indian cases of
Rett syndrome. Our study emphasizes the role of CDKL5 mutation screening in cases of
atypical Rett syndrome with congenital seizure variant.