Abstract
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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Change history
29 October 2008
NOTE: In the version of this article initially published, there was an error in the text on page 1066. The protein interacting with CASK is the CASK interacting nucleosome assembly protein (CINAP/TSPYL2) and not the TATA-binding protein associated factor TAF9. This error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
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.).
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Contributions
J.N. contributed to mutation analysis, X chromosome inactivation studies, in vitro splicing assay and manuscript writing. D.H. contributed to analysis of clinical data and manuscript writing and evaluated individual 2. I.W. contributed to FISH and mutation analysis and X chromosome inactivation studies. J.A.G. contributed to brain pathology of individual 5 and manuscript writing. V.V.C. contributed to analysis of Cask-KI mice. J.S. and S.L.C. interpreted the microarray, designed quantitative PCR assays and performed and interpreted the results in individual 3. R.U. contributed to design and production of BAC arrays. A.K. referred and evaluated individual 4. C.A.H. and A.F. contributed to obtaining and building up the Cask-KI mouse colony, genotyping of mice and preparing brains for morphological and histological analysis. L.R.C. referred and evaluated individual 5 and arranged for the brain to be obtained. G.U. interpreted brain scans of individual 4. U.F. referred and evaluated individual 1. E.K. performed and interpreted array CGH analysis for individuals 2 and 3 and FISH analysis for individual 2. W.B.D. contributed to patient ascertainment, clinical evaluation including interpretation of all brain scans, delineation of the phenotype, obtainment of the brain of individual 5, supervision of the mouse cerebellar studies and manuscript writing. K.K. designed the study, performed data analysis and contributed to manuscript writing.
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Supplementary Note, Supplementary Figures 1–5, Supplementary Tables 1–4, Supplementary Methods (PDF 4525 kb)
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Najm, J., Horn, D., Wimplinger, I. et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet 40, 1065–1067 (2008). https://doi.org/10.1038/ng.194
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DOI: https://doi.org/10.1038/ng.194
