title: 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.
authors.affiliation: Medical Genetics, University of Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.forename: Sara
authors.initials: S
authors.lastname: Azimonti
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bertani
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bolognese
authors.forename: Elena
authors.initials: E
authors.lastname: Colombo
authors.forename: Rossella
authors.initials: R
authors.lastname: Caselli
authors.forename: Elisa
authors.initials: E
authors.lastname: Scala
authors.forename: Ilaria
authors.initials: I
authors.lastname: Longo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grosso
authors.forename: Chiara
authors.initials: C
authors.lastname: Pescucci
authors.forename: Francesca
authors.initials: F
authors.lastname: Ariani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Hayek
authors.forename: Paolo
authors.initials: P
authors.lastname: Balestri
authors.forename: Anna
authors.initials: A
authors.lastname: Bergo
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Badaracco
authors.forename: Michele
authors.initials: M
authors.lastname: Zappella
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kilstrup-Nielsen
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Landsberger
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics*; D012640:Seizures / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human