CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome

Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Most patients affected by classic RTT and a smaller percentage of patients with the milder form 'preserved speech variant' have either point mutations or deletions/duplications in the MECP2 gene. Recently, mutations in the CDKL5 gene, coding for a putative kinase, have been found in female patients with a phenotype overlapping with that of RTT. Here, we report two patients with the early seizure variant of RTT, bearing two novel CDKL5 truncating mutations, strengthening the correlation between CDKL5 and RTT. Considering the similar phenotypes caused by mutations in MECP2 and CDKL5, it has been suggested that the two genes play a role in common pathogenic processes. We show here that CDKL5 is a nuclear protein whose expression in the nervous system overlaps with that of MeCP2, during neural maturation and synaptogenesis. Importantly, we demonstrate that MeCP2 and CDKL5 interact both in vivo and in vitro and that CDKL5 is indeed a kinase, which is able to phosphorylate itself and to mediate MeCP2 phosphorylation, suggesting that they belong to the same molecular pathway. Furthermore, this paper contributes to the clarification of the phenotype associated with CDKL5 mutations and indicates that CDKL5 should be analyzed in each patient showing a clinical course similar to RTT but characterized by a lack of an early normal period due to the presence of seizures.

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

“…12,13 To date, over 200 sequence variants or genomic deletions in CDKL5 have been reported in both female and male patients with X-linked dominant early-onset seizures manifesting before 5 months of age, severe intellectual disability with absent speech, and Rett-like features such as hand stereotypies and deceleration of head growth classified as Epileptic encephalopathy, early infantile, 2 (OMIM 300672) or Angelman syndrome-like (OMIM 105830). 7,[14][15][16][17][18] The phenotypic resemblance to Rett syndrome has been proposed to result from similar functions or interactions between CDKL5 and MECP2 in their molecular pathways during neurodevelopment (OMIM 30005); 4,13,[19][20][21][22][23] however, more studies are needed to verify this hypothesis. Most recently, Livide et al 24 showed that a subunit of glutamate receptor ligand-gated ion channel, GluD1, encoded by GRID1, is a commonly altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells and suggested that it could be a new therapeutic target for Rett syndrome.…”

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome

“…Several reports have identified large gene deletions in RTT patients that escaped detection by PCR-based screening strategies (Laccone et al 2004;Schollen et al 2003). Others have identified mutations in a novel MeCP2 isoform and in CDKL5 (Archer et al 2006a, b;Evans et al 2005a;Kriaucionis et al 2004;Mari et al 2005;Scala et al 2005;Tao et al 2004;Weaving et al 2004). This study reports the results of the mutation analysis of MECP2 and CDKL5 in 121 unrelated Chinese patients with classic or atypical RTT, conducted to obtain a genotypic representation of the mutational spectrum in this population.…”

An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain

“…[2][3][4][5][6][7][8] The gene is composed of 20 encoding exons, and so far 450 mutations in patients with CDKL5-related encephalopathy have been reported, affecting quasi-exclusively girls. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Patients with CDKL5 mutations typically present severe intellectual disability and early seizures, microcephaly in B1/3 of cases, as well as RTT-like features such as severe hypotonia, hand stereotypies and sleep disturbances. 22 Several patients having symptoms reminiscent of a CDKL5-related disease profile have had no mutation identified, in spite of the large screening strategy that is available, suggesting that other unexplored regions and/or genetic loci are involved in the disease.…”

“…6,23 CDKL5 phosphorylation targets are currently largely unknown. So far, it has been shown that the protein, in vitro, may autophosphorylate, and it phosphorylates the product of the methyl-CpG-binding protein 2 (MECP2, OMIM 300005) gene, which is mutated in 490% of classic RTT patients, 24 suggesting a common signaling pathway between these two proteins; 6,9,25 and the N-terminal region of the DNA methyltransferase 1 in nuclei. 26 In this study, we report the coincidental finding of an additional exon within the CDKL5 gene and describe its conservative feature in several species.…”