CASK is a multi-domain scaffolding protein that interacts with the transcription factor TBR1 and regulates expression of genes involved in cortical development such as RELN. Here we describe a previously unreported X-linked brain malformation syndrome caused by mutations of CASK. All five affected individuals with CASK mutations had congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia, and severe mental retardation.
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We are grateful to the study participants and their parents. We thank I. Jantke, L. Schroedter and F. Trotier for skillful technical assistance, S. Fuchs and K. Ziegler for chromosome analysis, and A. Nowka for help with the in vitro splicing assay. We also thank T. Südhof (Howard Hughes Medical Institute) for providing Cask knock-in mice. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (KU 1240/3-2 to K.K.), and a grant from the US National Institutes of Health/National Institute of Neurological Disorders and Stroke (R01-NS050375 to W.B.D.).