CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome.
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.
Mari
Francesca
F
Medical Genetics, University of Siena, Italy.
Azimonti
Sara
S
Bertani
Ilaria
I
Bolognese
Fabrizio
F
Colombo
Elena
E
Caselli
Rossella
R
Scala
Elisa
E
Longo
Ilaria
I
Grosso
Salvatore
S
Pescucci
Chiara
C
Ariani
Francesca
F
Hayek
Giuseppe
G
Balestri
Paolo
P
Bergo
Anna
A
Badaracco
Gianfranco
G
Zappella
Michele
M
Broccoli
Vania
V
Renieri
Alessandra
A
Kilstrup-Nielsen
Charlotte
C
Landsberger
Nicoletta
N
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
D017931:DNA Primers; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human