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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
References
Cox, J. et al. Trends Mol. Med. 12, 358–366 (2006).
Hevner, R.F. et al. Neurosci. Res. 55, 223–233 (2006).
Baala, L. et al. Nat. Genet. 39, 454–456 (2007).
Hsueh, Y.P. Curr. Med. Chem. 13, 1915–1927 (2006).
Hsueh, Y.P. et al. Nature 404, 298–302 (2000).
Froyen, G. et al. Hum. Mutat. 28, 1034–1042 (2007).
Atasoy, D. et al. Proc. Natl. Acad. Sci. USA 104, 2525–2530 (2007).
Laverty, H.G. et al. Genomics 53, 29–41 (1998).
D'Arcangelo, G. et al. Bioessays 20, 235–244 (1998).
Hevner, R.F. et al. Neuron 29, 353–366 (2001).
Hong, S.E. et al. Nat. Genet. 26, 93–96 (2000).
Cartegni, L. et al. Nat. Rev. Genet. 3, 285–298 (2002).
Franco, B. et al. Curr. Opin. Genet. Dev. 16, 254–259 (2006).
Bulfone, A. et al. Neuron 21, 1273–1282 (1998).
Leid, M. et al. Gene Expr. Patterns 4, 733–739 (2004).
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.).
Author information
Authors and Affiliations
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.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Note, Supplementary Figures 1–5, Supplementary Tables 1–4, Supplementary Methods (PDF 4525 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.194
This article is cited by
-
Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders
Molecular Neurobiology (2024)
-
KIRREL3-related disorders: a case report confirming the radiological features and expanding the clinical spectrum to a less severe phenotype
Italian Journal of Pediatrics (2023)
-
Drosophila CASK regulates brain size and neuronal morphogenesis, providing a genetic model of postnatal microcephaly suitable for drug discovery
Neural Development (2023)
-
A novel de novo variant in CASK causes a severe neurodevelopmental disorder that masks the phenotype of a novel de novo variant in EEF2
Journal of Human Genetics (2023)
-
A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: a case report and literature review
Italian Journal of Pediatrics (2022)