Human Molecular Genetics Advance Access originally published online on May 25, 2005
Human Molecular Genetics 2005 14(14):1935-1946; doi:10.1093/hmg/ddi198
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CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome
1Medical Genetics, 2Department of Pediatrics, University of Siena, Policlinico ‘Le Scotte’, 53100 Siena, Italy, 3Dipartimento di Biologia Strutturale e Funzionale, Università dell'Insubria, 21052 Busto Arsizio (VA), Italy, 4Department of Stem Cell Research, San Raffaele Scientific Institute, 20132 Milano, Italy and 5Child Neuropsychiatry, Azienda Ospedaliera Senese, 53100 Siena, Italy
* To whom correspondence should be addressed. Tel:+39 0331339406; Fax:+39 0331339459; Email: landsben{at}uninsubria.it
Received February 16, 2005; Revised April 14, 2005; Accepted May 16, 2005
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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