, Volume 12, Issue 2, pp 165–167

Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features


  • Nils Rademacher
    • Max Planck Institute for Molecular GeneticsDepartment of Human Molecular Genetics
  • Melanie Hambrock
    • Max Planck Institute for Molecular GeneticsDepartment of Human Molecular Genetics
  • Ute Fischer
    • Max Planck Institute for Molecular GeneticsDepartment of Human Molecular Genetics
  • Bettina Moser
    • Max Planck Institute for Molecular GeneticsDepartment of Human Molecular Genetics
  • Berten Ceulemans
    • Department of Neurology-Child NeurologyUniversity of Antwerp
  • Wolfgang Lieb
    • Institut für HumangenetikUniversität zu Lübeck
  • Rainer Boor
    • Klinik für NeuropädiatrieUniversitätsklinikum Schleswig-Holstein, Campus
  • Irina Stefanova
    • Institut für HumangenetikUniversität zu Lübeck
  • Gabriele Gillessen-Kaesbach
    • Institut für HumangenetikUniversität zu Lübeck
  • Charlotte Runge
    • Institut für HumangenetikUniversität zu Lübeck
  • Georg Christoph Korenke
    • Department of NeuropediatricsChildren’s Hospital
  • Stefanie Spranger
    • Praxis für Humangenetik
  • Franco Laccone
    • Department of Medical GeneticsMedical University of Vienna
  • Andreas Tzschach
    • Max Planck Institute for Molecular GeneticsDepartment of Human Molecular Genetics
    • Max Planck Institute for Molecular GeneticsDepartment of Human Molecular Genetics

DOI: 10.1007/s10048-011-0277-6

Cite this article as:
Rademacher, N., Hambrock, M., Fischer, U. et al. Neurogenetics (2011) 12: 165. doi:10.1007/s10048-011-0277-6


CDKL5Rett syndromeSeizuresInfantile spasms

Letter to the editor

Mutations in CDKL5, which encodes cyclin dependent kinase-like 5, cause a form of severe infantile epileptic encephalopathy (EIEE2, OMIM 300672) predominantly in girls [13]. The clinical consequences of CDKL5 mutations characteristically comprise infantile spasms, early-onset seizures, and severe mental retardation. Clinically, there is some overlap with Rett syndrome (RTT, OMIM 312750), and female patients with CDKL5 mutations are often considered as suffering from atypical RTT or the Hanefeld variant of RTT. Other genes associated with atypical RTT are FOXG1, MEF2C, and NTNG1 [4]. To date, about 80 patients have been reported with CDKL5 mutations. The distribution of mutations over most of the presently known coding exons indicates that there are no mutational hot-spots. The function of CDKL5/Cdkl5 is largely unexplored. Its gene product interacts with MeCP2, which is mutated in over 90% of patients with classic RTT. More recent studies have shown that CDKL5 controls the morphology of nuclear speckles [5] and that Cdkl5 is required for neuronal morphogenesis.

By performing RT-PCR experiments on mouse total brain RNA with different primer pairs, we obtained products of the expected size, but also an additional larger product in each reaction (data not shown). Sequencing of the larger products revealed an insertion of 123 bp between exons 16 and 17. We have termed this insert “exon 16a.” This exon is predicted to code for an in-frame addition of 41 amino acids into the presently known Cdkl5 gene variants (Fig. 1). In the meantime, Fichou et al. reported that in the mouse, Cdkl5 transcripts containing this exon are expressed in all brain regions tested [6]. RT-PCR analysis using RNA from different human brain regions and human embryonic kidney 293 cells demonstrated that this splice variant including the novel exon 16a (genomic position: chrX:18551920–18552042 according to hg18) is also expressed in humans (Fig 1). However, expression of the exon 16a containing isoform was barely detectable in a lymphoblastoid cell line of a healthy control (data not shown), suggesting tissue-restricted alternative splicing of CDKL5 and providing an explanation why this isoform had hitherto escaped detection. The nucleotide and amino acid sequences of exon 16a in mice and humans are highly conserved (96% identity) (Fig 1). CDKL5 mutation search including the newly found exon 16a in a cohort of 345 female patients who had clinical diagnoses of either RTT, severe infantile seizures or atypical RTT, revealed five novel CDKL5 mutations (c.884delC, p.P295LfsX54; c.1083insC, p.A362CfsX2; c.2529delA, p.L843FfsX19; c.400C>T, p.Arg134X; c.1648C>T, p.R550X). All five girls suffered from severe mental retardation and seizures with onset in infancy. Three patients were also microcephalic. The detailed clinical descriptions of the patients are given as supplemental information online. Although mutation analysis in the novel exon failed to reveal any aberrations in our patient cohort, the identification of a novel brain-expressed transcript including an additional in-frame exon will have implications for the diagnostics of patients with atypical Rett syndrome, and functional investigations of this novel isoform will expand our understanding of the biological role of CDKL5.
Fig. 1

a Results of the RT-PCR experiments using a primer specifc for the newly identified CDKL5 exon 16a. RNA samples of different human adult and fetal brain regions and HEK-T cells were used as templates. A specific product of expected size (263 bp) was amplified from all samples. NC negative control. b Alignment of CDKL5 exon 16a sequence (arrow) to the genomic sequence demonstrates the location of this exon within CDKL5 and high mammalian conservation. c Nucleotide and amino acid sequences of exon 16a in humans and mice


We are grateful to the patients and the parents of the families for their cooperation. We thank K. Hoffmann and S. Kübart for the excellent technical assistance.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10048_2011_277_MOESM1_ESM.doc (740 kb)
ESM 1(DOC 739 kb)

Copyright information

© Springer-Verlag 2011