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

Mutations in CDKL5, which encodes cyclin dependent kinase-like 5, cause a form of severe infantile epileptic encephalopathy (EIEE2, OMIM 300672) predominantly in girls [1–3]. 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 hotspots. 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 Electronic supplementary material The online version of this article (doi:10.1007/s10048-011-0277-6) contains supplementary material, which is available to authorized users. N. Rademacher :M. Hambrock :U. Fischer : B. Moser : A. Tzschach :V. M. Kalscheuer (*) Max Planck Institute for Molecular Genetics, Department of Human Molecular Genetics, Ihnestr. 73, D-14195 Berlin, Germany e-mail: kalscheu@molgen.mpg.de