Abstract
Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3ε) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.3 involving the PAFAH1B1 and/or YWHAE genes, and using a 'reverse genomics' approach, characterized the clinical consequences of these duplications. Increased PAFAH1B1 dosage causes mild brain structural abnormalities, moderate to severe developmental delay and failure to thrive. Duplication of YWHAE and surrounding genes increases the risk for macrosomia, mild developmental delay and pervasive developmental disorder, and results in shared facial dysmorphologies. Transgenic mice conditionally overexpressing LIS1 in the developing brain showed a decrease in brain size, an increase in apoptotic cells and a distorted cellular organization in the ventricular zone, including reduced cellular polarity but preserved cortical cell layer identity. Collectively, our results show that an increase in LIS1 expression in the developing brain results in brain abnormalities in mice and humans.
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Acknowledgements
We thank the participating families for their cooperation in the study, the members of the Chromosomal Microarray Analysis and Cytogenetic/FISH laboratories for technical assistance, G. Eichele for help with the in situ hybridization experiments, E. Arama and S. Haiderleu for useful comments and advice, S. McConnell for the Foxg1(Cre) mice and M. O'Gorman (Children's Memorial Hospital, Chicago) for assistance with specimen collection. The work was supported in part by the Israeli Science Foundation (grant no. 270/04 to O.R. and an equipment grant), the Foundation Jérôme Lejeune, the Minerva Foundation with funding from the Federal German Ministry for Education and Research, German-Israeli collaboration grant Gr-1905, March of Dimes grant 6-FY07-388, collaborative BSF grant 2007081 (to O.R. and J.R.L.), a grant from the Paul Godfrey Research Foundation in Children's Diseases, the Benoziyo Center for Neurological Diseases, the Kekst Center, the Forcheimer Center, a Weizmann-Pasteur collaborative grant, a research grant from the Michigan Women of Wisdom Fund to support Weizmann Women scientists, support from Maurice Janin, the Jewish Communal Fund, Albert Einstein College of Medicine of Yeshiva University, the David and Fela Shapell Family Center research grant for Genetic Disorders Research, grants DIGESIC-MEC BFU2005-09085 and Ingenio 2010 MEC-CONSOLIDER CSD2007-00023 (to S.M.), support from EU grant LSHG-CT-2004-512003, the Baylor Medical Genetics Laboratories, the Mental Retardation Developmental Disabilities Research Center (HD024064) and a Program Project grant (P01 HD39420) from the National Institute of Child Health and Human Development (to J.R.L.). O.R. is an Incumbent of the Bernstein-Mason professorial chair of Neurochemistry.
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Contributions
W.B. coordinated human studies and conducted real time RT-PCR assays. T.S. produced transgenic mice and conducted mouse studies. O.A.S. recruited patients and reviewed clinical data. F.Z. conducted high-density array CGH and breakpoint analyses. M.A.W. carried out cell culture. J.V.H. reviewed the MRI data. T.L., V.S. and S.M. assisted in mouse analyses. Y.Y. provided GAD67-GFP mice. D.A.P. and K.L.G. conducted SNP genotyping. M.M.N., V.A.S., S.S.A., S.K.S., D.J.H., D.-L.D.-S., M.H. and A.L.B. recruited and clinically characterized patients. S.W.C., X.-Y.L. and T.S. were involved in cytogenetic and clinical array CGH studies. J.R.L. and O.R. were involved in research design and data analyses. W.B., T.S., O.A.S., O.R. and J.R.L. prepared the manuscript.
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Supplementary Text and Figures
Supplementary Note, Supplementary Methods, Supplementary Table 1 and Supplementary Figures 1–5 (PDF 760 kb)
Supplementary Movie 1
Organotypic slice cultures prepared from brains of E13.5 control mice carrying a silent transgene (Cre negative). (MOV 1461 kb)
Supplementary Movie 2
Organotypic slice cultures prepared from brains of E13.5 LIS1 overexpressing embryos (LIS1::Foxg1(cre)). (MOV 1627 kb)
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Bi, W., Sapir, T., Shchelochkov, O. et al. Increased LIS1 expression affects human and mouse brain development. Nat Genet 41, 168–177 (2009). https://doi.org/10.1038/ng.302
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DOI: https://doi.org/10.1038/ng.302
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