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Impairment of CDKL5 nuclear localization as a cause for severe infantile encephalopathy
  1. Haydee Rosas-Vargas (rosas{at}cochin.inserm.fr)
  1. Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France., France
    1. Nadia Bahi-Buisson (nadia.bahi-buisson{at}nck.ap-hop-paris.fr)
    1. Department of Neuropediatrics, Necker-Enfants Malades Hospital, Paris, France., France
      1. Christophe Philippe (c.philippe{at}chu-nancy.fr)
      1. Laboratoire de Génétique, EA3441, CHU Brabois, Vandoeuvre Les Nancy, France., France
        1. Juliette Nectoux (juliette_nectouxfr{at}yahoo.fr)
        1. Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France, France
          1. Benoit Girard
          1. AP-HP, Hôpital Cochin, Laboratoire de Biochimie et Génétique Moléculaire, France
            1. Marie Ange N'Guyen Morel (manguyen{at}chu-grenoble.fr)
            1. Service de Pédiatrie, CHU Grenoble, Grenoble, France, France
              1. Cyril Gitiaux (cyril.gitiaux{at}nck.aphp.fr)
              1. Department of Neuropediatrics, Necker Enfants Malades Hospital, Paris, France., France
                1. Leïla Lazzaro
                1. CHU Grenoble, France
                  1. Sylvie Odent
                  1. CHU Grenoble, France
                    1. Philippe Jonveaux
                    1. Laboratoire de Génétique, EA3441, CHU Brabois, Vandoeuvre Les Nancy, France., France
                      1. Jamel Chelly (chelly{at}cochin.inserm.fr)
                      1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
                        1. Thierry Bienvenu (bienvenu{at}cochin.inserm.fr)
                        1. Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France., France

                          Abstract

                          Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause infantile spasms as well as Rett syndrome-like phenotype. To date, less than twenty different mutations have been reported. So far, no clear genotype-phenotype correlation has been established. We screened the entire coding region of CDKL5 in 151 affected girls with a clinically heterogeneous phenotype ranging from encephalopathy with epilepsy to atypical Rett syndrome by denaturing high liquid performance chromatography and direct sequencing, and we identified three novel missense mutations located in catalytic domain (p.Ala40Val, p.Arg65Gln, p.Leu220Pro). Segregation analysis showed that p.Arg65Gln was inherited from the healthy father, which rules out the involvement of CDKL5 in the aetiology of the phenotype in this patient. However, the de novo occurrence was shown for p.Ala40Val and p.Leu220Pro. The p.Ala40Val mutation was observed in two unrelated patients and represented the first recurrent mutation in the CDKL5 gene. For the two de novo mutations, we analysed the cellular localization of the wild-type and CDKL5 mutants by transfection experiments. We showed that the two CDKL5 mutations cause mislocalization of the mutant CDKL5 proteins in the cytoplasm. Interestingly these missense mutations that result in a mislocalization of the CDKL5 protein are associated with severe developmental delay which was apparent within the first months of life characterized by early and generalized hypotonia, and autistic features, and as well as early infantile spasms.

                          • CDKL5
                          • MECP2
                          • Mislocalisation
                          • Rett syndrome
                          • Seizures

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