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Título

Duplications in the 17p13.3 Miller-Dieker syndrome region: Increased expression of LIS1 affects human and mouse brain development

Autor Bi, Weimin; Sapir, Tamar; Shchelochkov, Oleg A.; Zhang, Feng; Withers, Marjorie A.; Hunter, Jill V.; Levy, Talia; Shinder, Vera; Peiffer, Daniel A.; Gunderson, Kevin L.; Lu, Xin-Yan; Sahoo, Trilochan; Yanagawa, Yuchio; Beaudet, Arthur L.; Cheung, Sau Wai; Martínez, Salvador; Lupski, James R.; Reiner, Orly
Fecha de publicación nov-2008
EditorAmerican Society of Human Genetics
Citación ASHG 58th Annual Meeting 2008, Poster 1083/W
ResumenDeletions of the LIS1 gene in human chromosome 17p13.3 result in isolated lissencephaly sequence and the extended deletions including the 14-3-3ε gene cause Miller-Dieker syndrome (MDS). By array CGH we identified seven unrelated cases with duplication ranging from 240 kb to 3.6 Mb in 17p13.3 involving the LIS1 and/or the 14-3-3ε genes. Duplications in three cases are complex and may represent the autosomal rearrangements generated by the DNA replication FoSTeS mechanism. Real-time RT-PCR showed that the expression levels of the LIS1, 14-3-3ε, and CRK genes were increased when these genes are duplicated. Using a “forward genomics” approach we characterized the clinical consequences of duplications. Increased LIS1 dosage causes smaller brains, mild brain structural abnormalities, moderate to severe developmental delay, and failure to thrive. Duplication of 14-3-3ε and surrounding genes increases the risk for macrosomia, mild developmental delay, pervasive developmental disorder, and results in shared facial dysmorphologies. Transgenic mice conditionally over-expressing LIS1 in the developing brain exhibited a decrease in brain size, an increase in apoptotic cells, and a distorted cellular organization in the ventricular zone including reduced cellular polarity. Collectively, our results show that an increase in LIS1 expression in the developing brain results in smaller brains and neuronal migration abnormalities in mice and human patients.
Descripción Poster presentado en la 58th Annual Meeting of the American Society of Human Genetics (ASHG 2008), Philadelphia, PA, Nov 11-15, 2008.
Versión del editorhttp://www.ashg.org/2008meeting/
URI http://hdl.handle.net/10261/9516
Aparece en las colecciones: (IN) Comunicaciones congresos
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